Role of Mevalonate Pathway in Pancreatic Cancer: Comparison
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Pancreatic cancer’s substantial impact on cancer-related mortality, responsible for 8% of cancer deaths and ranking fourth in the US, persists despite advancements, with a five-year relative survival rate of only 11%. The mevalonate pathway and its components play crucial roles in the development and progression of pancreatic cancer. Targeting cholesterol metabolism, particularly through the use of statins, holds promise as a therapeutic strategy.

  • pancreatic cancer
  • lipid metabolism
  • cholesterol metabolism
  • mevalonate pathway
  • lipoprotein

1. Introduction

Pancreatic cancer represents currently 8% of cancer-related deaths and is the fourth leading cause in the United States [1]. The 5-year relative survival rate is still only around 11% [1]. According to the International Agency for Research on Cancer (IARC), the global number of annual new cases and pancreatic cancer-related deaths from 2020 to 2040 is predicted to increase by 70% (496,000–844,000) and 72% (466,000–801,000), respectively [2]. Deregulating cellular metabolism and immune evasion are some of the core hallmarks of cancer [3]. It is evident that cancer cells need to keep generating cellular components such as DNA, proteins, and lipids to enable rapid cell growth [4]. It has been demonstrated that the tumor-adjacent exocrine tissue exhibits upregulation of proteins related to lipid transport, which is associated with shorter post-operative survival in pancreatic cancer patients [5]. Cholesterol is an essential structural component of cell membranes and is important for physiological function [6]. 7-dehydroxycholesterol is the precursor for vitamin D and cholesterol, which itself is the key precursor for several important molecules such as bile acids as well as hormones such as glucocorticoid, mineralocorticoid, progesterone, estrogen, and testosterone [7]. Yet, growing evidence indicates that increased cholesterol flux is a common feature of cancer, and targeting the cholesterol biosynthesis pathway has been considered a promising therapeutic strategy [8].

2. The Role of the Mevalonate Pathway and De Novo Cholesterol Synthesis in Pancreatic Cancer

Acetyl coenzyme A (Acetyl-CoA) is the central molecule that participates in fatty acid synthesis as well as cholesterol biosynthesis [4]. Acetyl-CoA abundance is elevated in acinar cells of the pancreatic cancer mouse model called KC (Pdx1-Cre; lox-stop-lox-KrasG12D/+), and acetyl-CoA in the cholesterol biosynthesis pathway supports acinar-to-ductal metaplasia (ADM) formation [9]. ADM is the precursor for pancreatic intraepithelial neoplasia (PanIN), which can further progress to invasive pancreatic cancer [10]. Acetyl-CoA is also a substrate for histone acetyltransferases (HATs). Histone acetylation can lead to changes in gene expression associated with ADM formation. The oncogenic KrasG12D mutation is sufficient to promote histone H4 and histone H3 lysine 27 acetylation in acinar cells [9]. Histone acetylation marks are “written” by HATs and “read” by bromodomains cooperatively regulating transcription [11]. Bromodomain and Extra-Terminal motif (BET) protein inhibitor JQ1 prevent interaction between BET protein, acetylated histone, and transcription factors [12] and ADM formation [9]. These data emphasize the roles of acetyl-CoA and epigenetic regulations in the early stage of pancreatic carcinogenesis. Yet, the role of acetyl-CoA as a central source in cholesterol biosynthesis is also of significant importance in pancreatic cancer development, as the inhibition of cholesterol biosynthesis-associated enzymes attenuates ADM formation [9]. This chapter will summarize and discuss the critical roles of enzymes involved in the mevalonate pathway and de novo cholesterol synthesis in pancreatic cancer. In the first step, the enzyme acetoacetyl-CoA thiolase (also known as acetyl-CoA acetyltransferase, ACAT1 in mitochondria, ACAT2 in the cytosol) catalyzes a process to generate acetoacetyl-CoA (C4) from two acetyl-CoA molecules [6] (Figure 1). Sterol O-Acyltransferase 1 (encoded by the SOAT1 gene, also known as Acyl-CoA cholesterol acyltransferase), which converts excess cholesterol to inert cholesterol esters, is also known as “ACAT1”. In the current rteview articlext, however, ACAT indicates acetyl-CoA acetyltransferase but not acyl-CoA cholesterol acyltransferase. ACAT1 is activated in several cancer types. Y407 phosphorylation of the ACAT1-tetramer by epidermis growth factor (EGF) stabilizes the active ACAT1-tetramer and supports cancer cell proliferation and tumor growth [13]. ACAT1 also possesses lysine acetyltransferase activity, which acetylates pyruvate dehydrogenase (PDHA1) and pyruvate dehydrogenase phosphatase (PDP1), leading to inhibition of the pyruvate dehydrogenase complex (PDC) activity [14]. As PDC plays a key link between glycolysis and the tricarboxylic acid (TCA) cycle, inhibition of PDC activity contributes to the Warburg effect [14]. The role of ACAT2 in pancreatic cancer and cancer development has not been fully elucidated. So far, it has been shown that elevated ACAT2 gene expression is associated with radiotherapy resistance in pancreatic cancer cells [15]. Since the cytosolic ACAT2 enzyme is involved in cholesterol synthesis but the mitochondrial ACAT1 plays a more prominent role in cancer, it may be possible that cancer cells take advantage of ACAT2-mediated attenuated PDC activity rather than enhanced ACAT2 activity for cholesterol synthesis.
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Figure 1. The cholesterol synthesis pathway. Enzymes involved in the reaction are colored in blue, and inhibitors and inhibition symbols are colored in red. Enzymes involved in ketone body biosynthesis, such as HMG-CoA lyase and β-hydroxybutylate dehydrogenase, are also included in the figure. ACAT: acetoacetyl-CoA thiolase; HMG-CoA: 3-hydroxy-3methylglutaryl-CoA.
Subsequently, 3-hydroxy-3methylglutaryl-CoA (HMG-CoA) synthase (HMGCS1) catalyzes the condensation of acetoacetyl-CoA and acetyl-CoA molecules to form HMG-CoA (C6) and CoA [6] (Figure 1). Expression of the HMGCS1 gene is higher in pancreatic cancer patients, which is associated with shorter disease-free survival [16]. CRISPR-Cas9-mediated knockout of HMGCS1 suppresses the proliferation of gastric cancer cells [17]. Further, HMGCS1 can induce transcriptional upregulation of pluripotency genes POU5F1 (Oct4) and SOX2 [17] and is a key mediator of cancer stem cell enrichment in breast cancer [18]. These data suggest that HMGCS1 contributes to cancer in metabolic and non-metabolic ways. HMGCS1 drives drug resistance and is suggested to serve as a target for the treatment of acute myeloid leukemia patients [19]. Hymeglusin (L-659,699) is the specific HMGCS1 inhibitor [20], and hymeglusin enhances the therapeutic efficacy of venetoclax in acute myeloid leukemia [21]. Whether hymeglucin can inhibit pancreatic cancer development and progression needs to be clarified. Conversion of HMG-CoA to acetoacetate and acetyl-CoA is catalyzed by HMG-CoA lyase (encoded by the HMGCL gene). HMGCL is a key enzyme in ketogenesis. Acetoacetate will be converted into β-hydroxybutylate catalyzed by β-hydroxybutylate dehydrogenase, which plays an important role in pancreatic cancer. HMGCL protein level is high in pancreatic cancer in mice (Pdx1-Cre; lox-stop-lox-KrasG12D/+; Ink4a/Arflox/lox). HMGCL and β-hydroxybutylate contribute to pancreatic tumor aggressiveness and support metastatic dissemination [22]. Further studies to explore the molecular mechanisms regulated by HMGCL are required to validate HMGCL as a druggable candidate to target pancreatic cancer [22]. HMG-CoA reductase (HMGCR) regulates the conversion of HMG-CoA to mevalonate. HMGCR is the NADPH-dependent rate-limiting enzyme in the mevalonate pathway and is important for the further generation of the isoprenoid products (geranyl pyrophosphate and farnesyl pyrophosphate) [6] (Figure 1). Pancreatic expression of Hmgcr is upregulated in a murine spontaneous pancreatic cancer model (Pdx1-Cre; lox-stop-lox-KrasG12D/+; Ink4a/Arflox/lox) [23], as well as in pancreatic cancer patients [24]. As HMGCR is the master regulator in the mevalonate pathway for cholesterol synthesis, several HMGCR inhibitors, such as statins, have been considered as cholesterol-lowering agents as well as anti-cancer drugs. An HMGCR inhibitor, simvastatin (Table 1), delays PanIN progression in KC mice (Pdx1-Cre; lox-stop-lox-KrasG12D/+) and attenuates pancreatic cancer development in KPC (Pdx1-Cre; lox-stop-lox-KrasG12D/+; lox-stop-lox-Trp53R172H/+) mice [25]. Another HMGCR inhibitor, atorvastatin, also inhibits cancer development and increases the survival of KPC mice [26]. In addition to simvastatin and atorvastatin, several statins have been approved by the FDA, namely rosuvastatin, pravastatin, fluvastatin, lovastatin, and pitavastatin [27]. High expression of HMGCR is not associated with shorter survival in pancreatic cancer patients [24]. Yet, an updated meta-analysis of 26 studies with more than 170,000 pancreatic cancer patients suggests a significant decrease in the risk of pancreatic cancer with statin use [28]. Mechanistically, it has been shown that atorvastatin inhibits Akt signaling via the P2X7 receptor in human pancreatic cancer cells, and expression of Akt and the P2rx7 gene is also down-regulated in atorvastatin-fed Ptf1a-Cre; lox-stop-lox-KrasG12D/+ mice [29][30]. Statins further decrease PD-L1 expression via JNK upregulation and TAZ downregulation [31]. In a pancreatic cancer xenograft mouse model, combination therapy with simvastatin and anti-PD-1 showed an enhanced anti-tumor effect compared to simvastatin or anti-PD-1 mono-therapeutic treatment [31]. Statin treatment can, however, induce compensatory increases in HMGCR also in pancreatic cancer [32]. It has been shown that the compensatory and counter mechanisms of the cells to maintain cholesterol levels induce an epithelial-to-mesenchymal transition (EMT)-like cell state and trap pancreatic cancer cells in a mesenchymal-like state. Several pancreatic cancer cell lines are capable of ERK activation upon statin treatment, leading to increased metastatic seeding ability through enhanced migration, extravasation, and survival. Since cancer cells are trapped in a mesenchymal-like state, they are unable to undergo a mesenchymal-to-epithelial transition (MET), and therefore statins inhibit the formation of metastatic colonies [32]. To eliminate the statin-induced accumulation of HMGCR, a sterol analog as a potent HMGCR degrader named compound 81 has been identified [33]. Further studies are needed to clarify whether inhibition of compensatory accumulation of HMGCR can further decrease pancreatic cancer risk. Mevalonate will be further phosphorylated by mevalonate kinase (MVK) and subsequently by phosphomevalonate kinase (PMVK) to form mevalonate-5-phosphate and mevalonate-5-pyrophosphate (C6), respectively. Mevalonate-5-pyrophosphate decarboxylase (also known as mevalonate diphosphate decarboxylase, MVD) catalyzes the reaction from mevalonate-5-pyrophosphate to generate isopentenyl-5-pyrophosphate (C5). Isopentenyl-5-pyrophosphate will be converted to demethylallyl pyrophosphate by isopentenyl-diphosphate isomerase (IDI) [6] (Figure 1). There have been two IDI members identified: IDI1 and IDI2, IDI1 is found in most eukaryotes [34]. In humans, it has been shown that IDI2 is expressed only in skeletal muscle [35]. Farnesyl diphosphate synthase (coded by the FDPS gene) catalyzes a chain elongation from isopentenyl-5-pyrophosphate and demethylallyl pyrophosphate to produce geranyl pyrophosphate (C10). FDPS forms farnesyl pyrophosphate (C15) from geranyl pyrophosphate and an additional isopentenyl-5-pyrophosphate molecule [6] (Figure 1). The potential role of MVK, PMVK, MVD, IDI, or FDPS in pancreatic cancer has not been fully addressed. In the case of liver cancer, it has been shown that the PMVK protein level is higher in tumors than in non-tumor areas. High PMVK expression is associated with shorter survival in liver cancer patients. Mechanistically, PMVK phosphorylates β-catenin and enhances its stability. Mevalonate-5-pyrophosphate also stabilizes β-catenin by inhibition of casein kinase 1 alpha 1 (CKIa, encoded by the CSNK1A1 gene)-mediated S45 phosphorylation of β-catenin. This prevents proteolytic degradation of β-catenin [36]. Hepatic Pmvk knockout or intraperitoneal administration of small PMVK inhibitor named PMVKi5 (C24H23ClN2O6,N-[(E)-[3-[(4-chloro-3,5-dimethylphenoxy)methyl]-4-methoxyphenyl]methylideneamino]-3,4,5-trihydroxybenzamide) attenuates hepatocarcinogen diethylnitrosamine and carbon tetrachloride-induced hepatocellular carcinogenesis [36]. In the case of prostate cancer, it has been shown that FDPS is associated with PTEN loss and Akt activation [37]. EGF-induced cancer cell invasion requires Ras homolog (Rho) GTPases-mediated actin-cytoskeltal reorganization. For membrane attachment and biological activity, Rho GTPases require posttranslational modifications to provide a lipophilic anchor [38]. Rho can be geranylgeranylated, and Ras can be farnesylated [39]. Oncogenic KRAS mutations are observed in more than 90% of pancreatic cancer patients; among those, the KRASG12D mutation is the most common and present in nearly 40% of pancreatic cancer patients [40]. A small molecule KRASG12D inhibitor MRTX1133 has been generated and specificity and efficacy have been preclinically proven [41]. Yet, targeting KRAS farnesylation to globally modulate KRAS activity could also be a therapeutic option for pancreatic cancer. KRAS requires farnesylation for membrane localization, and therefore farnesyltransferase inhibitors have been developed to block the membrane translocation. However, farnesyltransferase inhibitor treatment causes KRAS geranylgeranylation to become active; therefore, a dual farnesyltransferase and geranylgeranyl-transferase inhibitor named FGTI-2734 has been developed [42]. FGTI-2734 attenuates Akt, mTOR, and c-Myc signaling activity and inhibits the growth of pancreatic cancer patient-derived xenografts with KRASG12D or KRASG12V mutation [42]. Further preclinical and clinical studies are needed to validate the anti-cancer effects of FGTI-2734. The role of MVK, PMVK, MVD, IDI, or FDPS in producing geranyl pyrophosphate and farnesyl pyrophosphate in pancreatic cancer also needs to be clarified. Geranyl pyrophosphate and farnesyl pyrophosphate are key intermediates in cholesterol synthesis but also for post-translational modifications. Squalene synthase (also known as farnesyl-diphosphate farnesyltransferase 1, coded by the FDFT1 gene) catalyzes a reductive dimerization of two farnesyl pyrophosphate molecules to form squalene (C30) in a NADPH-dependent manner [6] (Figure 1). Pancreatic cancer patients with high levels of FDFT1 expression show significantly shorter overall survival [43]. Interestingly, in murine pancreatic cancer autochthonous model (Ptf1a-Cre; lox-stop-lox-KrasG12D/+; Trp53lox/+), CRISPR-Cas9 screening for targeting ca. 3000 metabolic genes identified Fdft1 as one of the most differentially dependent genes in vivo. Fdft1 knockout shows no decrement in 2D tumor cell proliferation but exhibits growth inhibition in 3D culture and orthotopic transplanted tumor cells [43]. Loss of Fdft1 does not affect the famesylation of Ras but attenuates activation of the Akt signaling pathway [43]. Administration with an FDFT1 inhibitor TAK-475 (1-[2-[(3R,5S)-1-[3-(Acetyloxy)-2,2-dimethylpropyl]-7-chloro-5-(2,3-dimethoxyphenyl)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-yl]acetyl]-4-piperidineacetic acid, lapaquistat acetate) reduces subcutaneous transplanted pancreatic tumor cell growth and incubation of 3D pancreatic tumor cells with TAK-475 reduces activation of the Akt signaling pathway [43]. For colon cancer, it has been shown that patients with high FDFT1 protein expression show significantly shorter overall and relapse-free survival than patients with low FDFT1 expression [44]. Squalene epoxidase (also known as squalene monooxigenase, coded by the SQLE gene) NADPH-dependently oxidizes squalene to 2,3-oxidosqualese (squalene epoxide) [6] (Figure 1). Pancreatic cancer patients exhibit high expression of SQLE, and high expression of SQLE is associated with shorter overall survival and disease-free survival of pancreatic cancer patients, high protein expression of SQLE exhibits shorter overall survival than patients with low SQLE expression [45][46][47]. SQLE promotes the proliferation and invasion of pancreatic cancer cells [46]. Mechanistically, SQLE attenuates the unfolded protein response pathway and activates the Akt signaling pathway [47]. An antifungal drug terbinafine has been widely used as a SQLE inhibitor. Terbinafine attenuates SQLE-induced pancreatic cancer cell proliferation and invasion [46]. Further, terbinafine augments the sensitivity of several chemotherapeutic drugs (e.g., cisplatin, 5-FU, gemcitabine) in pancreatic cancer cells [48]. Transcription of SQLE is directly repressed by p53 [49]. For other tumor entities such as liver cancer, it has been shown that terbinafine attenuates high-fat diet-mediated liver cancer development in p53 knockout mice (Alb-Cre; Trp53lox/lox) [49]. Terbinafine reduces tumor incidence and tumor number in diethynitrosoamine-injected, high-fat high-cholesterol diet-fed Sqle transgenic mice (Alb-Cre; Rosa26-lox-stop-lox-Sqle-IRES) [50]. Colorectal cancer patients with high SQLE expression (both RNA and protein levels) also exhibit shorter overall survival than patients with low SQLE expression [51]. Terbinafine attenuates the cell viability of colorectal cancer organoids as well as xenotransplanted tumor development and enhances chemosensitivity to 5-FU or oxaliplatin treatment [51]. On the contrary, another study showed that the median survival of colorectal cancer patients with high SQLE mRNA levels is longer than those with low SQLE expression [52]. Taken together, the role of SQLE in cancer is cancer type-specific or context-specific. In the case of pancreatic cancer, tumor-promoting and chemotherapeutic drug resistance have been shown. Lanosterol synthase (encoded by the LSS gene) converts squalene epoxide to lanosterol [6] (Figure 1). In the final step, the conversion from lanosterol into cholesterol is catalyzed by a number of enzymes via the so-called Bloch pathway and the Kandutsch-Russell pathway, where, in several steps, NADPH is required [53]. MM0299 inhibits LSS and diverts sterol flux from the Bloch pathway into the Shunt pathway, leading to commutation in 24(S),25-epoxycholesterol (EPC) [54] (Figure 1). So far, whether MM0299 has anti-tumor effects in pancreatic cancer has not been clarified. Taken together, enzymes involved in the mevalonate pathway and cholesterol synthesis contribute to ADM and PanIN formation as well as pancreatic cancer progression, metastasis, and chemoresistance. Some enzymes are additionally involved in the Warburg effect, post-translational and epigenetic regulations, and further investigation is needed to better understand the shared and distinct molecular function between each enzyme involved in the mevalonate pathway and cholesterol synthesis.
Table 1. Inhibitors related to cholesterol metabolism.
Intervention/Treatment Target Reference
Simvastatin HMGCR [25][27][55]
Atorvastatin HMGCR [26][27]
Rosuvastatin HMGCR [27]
Pravastatin HMGCR [27]
Fluvastatin HMGCR [27]
Lovastatin HMGCR [27]
Pitavastatin HMGCR [27]
Cmpd81 HMGCR (degradation) [33]
PMVKi5 PMVK [36]
TAK-475 FDFT1 [43]
terbinafine SQLE [46][48][50][51]
MM0299 LSS [54]
Avasimibe SOAT1 [56][57]
Surface anchor-engineered T cells with liposomal avasibime SOAT1 [58]
CP-113,818 SOAT1 [57]
K-604 SOAT1 [57]
Nilotinib SOAT1 [59]
Alirocumab PCSK9 [60]
Evolocumab PCSK9 [60]
R-IMPP PCSK9 [55]
PF-06446846 PCSK9 [55]

References

  1. Siegel, R.L.; Miller, K.D.; Wagle, N.S.; Jemal, A. Cancer statistics, 2023. CA Cancer J. Clin. 2023, 73, 17–48.
  2. International Cancer Research Association. Available online: https://gco.iarc.fr/tomorrow/en (accessed on 1 August 2023).
  3. Hanahan, D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022, 12, 31–46.
  4. Sunami, Y.; Rebelo, A.; Kleeff, J. Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells. Cancers 2017, 10, 3.
  5. Pirhonen, J.; Szkalisity, Á.; Hagström, J.; Kim, Y.; Migh, E.; Kovács, M.; Hölttä, M.; Peränen, J.; Seppänen, H.; Haglund, C.; et al. Lipid Metabolic Reprogramming Extends beyond Histologic Tumor Demarcations in Operable Human Pancreatic Cancer. Cancer Res. 2022, 82, 3932–3949.
  6. Cerqueira, N.M.; Oliveira, E.F.; Gesto, D.S.; Santos-Martins, D.; Moreira, C.; Moorthy, H.N.; Ramos, M.J.; Fernandes, P.A. Cholesterol Biosynthesis: A Mechanistic Overview. Biochemistry 2016, 55, 5483–5506.
  7. Mayengbam, S.S.; Singh, A.; Pillai, A.D.; Bhat, M.K. Influence of cholesterol on cancer progression and therapy. Transl. Oncol. 2021, 14, 101043.
  8. Juarez, D.; Fruman, D.A. Targeting the Mevalonate Pathway in Cancer. Trends Cancer 2021, 7, 525–540.
  9. Carrer, A.; Trefely, S.; Zhao, S.; Campbell, S.L.; Norgard, R.J.; Schultz, K.C.; Sidoli, S.; Parris, J.L.D.; Affronti, H.C.; Sivanand, S.; et al. Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis. Cancer Discov. 2019, 9, 416–435.
  10. Storz, P. Acinar cell plasticity and development of pancreatic ductal adenocarcinoma. Nat. Rev. Gastroenterol. Hepatol. 2017, 14, 296–304.
  11. Marmorstein, R.; Zhou, M.M. Writers and readers of histone acetylation: Structure, mechanism, and inhibition. Cold Spring Harb. Perspect. Biol. 2014, 6, a018762.
  12. Shi, J.; Vakoc, C.R. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol. Cell 2014, 54, 728–736.
  13. Fan, J.; Lin, R.; Xia, S.; Chen, D.; Elf, S.E.; Liu, S.; Pan, Y.; Xu, H.; Qian, Z.; Wang, M.; et al. Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth. Mol. Cell 2016, 64, 859–874.
  14. Goudarzi, A. The recent insights into the function of ACAT1: A possible anti-cancer therapeutic target. Life Sci. 2019, 232, 116592.
  15. Souchek, J.J.; Baine, M.J.; Lin, C.; Rachagani, S.; Gupta, S.; Kaur, S.; Lester, K.; Zheng, D.; Chen, S.; Smith, L.; et al. Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitisation. Br. J. Cancer 2014, 111, 1139–1149.
  16. Zhou, C.; Wang, Z.; Cao, Y.; Zhao, L. Pan-cancer analysis reveals the oncogenic role of 3-hydroxy-3-methylglutaryl-CoA synthase 1. Cancer Rep. 2022, 5, e1562.
  17. Wang, I.H.; Huang, T.T.; Chen, J.L.; Chu, L.W.; Ping, Y.H.; Hsu, K.W.; Huang, K.H.; Fang, W.L.; Lee, H.C.; Chen, C.F.; et al. Mevalonate Pathway Enzyme HMGCS1 Contributes to Gastric Cancer Progression. Cancers 2020, 12, 1088.
  18. Walsh, C.A.; Akrap, N.; Garre, E.; Magnusson, Y.; Harrison, H.; Andersson, D.; Jonasson, E.; Rafnsdottir, S.; Choudhry, H.; Buffa, F.; et al. The mevalonate precursor enzyme HMGCS1 is a novel marker and key mediator of cancer stem cell enrichment in luminal and basal models of breast cancer. PLoS ONE 2020, 15, e0236187.
  19. Zhou, C.; Li, J.; Du, J.; Jiang, X.; Xu, X.; Liu, Y.; He, Q.; Liang, H.; Fang, P.; Zhan, H.; et al. HMGCS1 drives drug-resistance in acute myeloid leukemia through endoplasmic reticulum-UPR-mitochondria axis. Biomed. Pharmacother. 2021, 137, 111378.
  20. Greenspan, M.D.; Yudkovitz, J.B.; Lo, C.Y.; Chen, J.S.; Alberts, A.W.; Hunt, V.M.; Chang, M.N.; Yang, S.S.; Thompson, K.L.; Chiang, Y.C.; et al. Inhibition of hydroxymethylglutaryl-coenzyme A synthase by L-659,699. Proc. Natl. Acad. Sci. USA 1987, 84, 7488–7492.
  21. Zhou, C.; Wang, Z.; Yang, S.; Li, H.; Zhao, L. Hymeglusin Enhances the Pro-Apoptotic Effects of Venetoclax in Acute Myeloid Leukemia. Front. Oncol. 2022, 12, 864430.
  22. Gouirand, V.; Gicquel, T.; Lien, E.C.; Jaune-Pons, E.; Da Costa, Q.; Finetti, P.; Metay, E.; Duluc, C.; Mayers, J.R.; Audebert, S.; et al. Ketogenic HMG-CoA lyase and its product β-hydroxybutyrate promote pancreatic cancer progression. EMBO J. 2022, 41, e110466.
  23. Guillaumond, F.; Bidaut, G.; Ouaissi, M.; Servais, S.; Gouirand, V.; Olivares, O.; Lac, S.; Borge, L.; Roques, J.; Gayet, O.; et al. Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma. Proc. Natl. Acad. Sci. USA 2015, 112, 2473–2478.
  24. Gunda, V.; Genaro-Mattos, T.C.; Kaushal, J.B.; Chirravuri-Venkata, R.; Natarajan, G.; Mallya, K.; Grandgenett, P.M.; Mirnics, K.; Batra, S.K.; Korade, Z.; et al. Ubiquitous Aberration in Cholesterol Metabolism across Pancreatic Ductal Adenocarcinoma. Metabolites 2022, 12, 47.
  25. Fendrich, V.; Sparn, M.; Lauth, M.; Knoop, R.; Plassmeier, L.; Bartsch, D.K.; Waldmann, J. Simvastatin delay progression of pancreatic intraepithelial neoplasia and cancer formation in a genetically engineered mouse model of pancreatic cancer. Pancreatology 2013, 13, 502–507.
  26. Liao, J.; Chung, Y.T.; Yang, A.L.; Zhang, M.; Li, H.; Zhang, W.; Yan, L.; Yang, G.Y. Atorvastatin inhibits pancreatic carcinogenesis and increases survival in LSL-KrasG12D-LSL-Trp53R172H-Pdx1-Cre mice. Mol. Carcinog. 2013, 52, 739–750.
  27. Sizar, O.; Khare, S.; Jamil, R.T.; Talati, R. Statin Medications. In StatPearls ; StatPearls Publishing: Treasure Island, FL, USA, 2023.
  28. Zhang, Y.; Liang, M.; Sun, C.; Qu, G.; Shi, T.; Min, M.; Wu, Y.; Sun, Y. Statin Use and Risk of Pancreatic Cancer: An Updated Meta-analysis of 26 Studies. Pancreas 2019, 48, 142–150.
  29. Mistafa, O.; Stenius, U. Statins inhibit Akt/PKB signaling via P2X7 receptor in pancreatic cancer cells. Biochem. Pharmacol. 2009, 78, 1115–1126.
  30. Mohammed, A.; Qian, L.; Janakiram, N.B.; Lightfoot, S.; Steele, V.E.; Rao, C.V. Atorvastatin delays progression of pancreatic lesions to carcinoma by regulating PI3/AKT signaling in p48Cre/+ LSL-KrasG12D/+ mice. Int. J. Cancer 2012, 131, 1951–1962.
  31. Uemura, N.; Hayashi, H.; Liu, Z.; Matsumura, K.; Ogata, Y.; Yasuda, N.; Sato, H.; Shiraishi, Y.; Miyata, T.; Nakagawa, S.; et al. Statins exert anti-growth effects by suppressing YAP/TAZ expressions via JNK signal activation and eliminate the immune suppression by downregulating PD-L1 expression in pancreatic cancer. Am. J. Cancer Res. 2023, 13, 2041–2054.
  32. Dorsch, M.; Kowalczyk, M.; Planque, M.; Heilmann, G.; Urban, S.; Dujardin, P.; Forster, J.; Ueffing, K.; Nothdurft, S.; Oeck, S.; et al. Statins affect cancer cell plasticity with distinct consequences for tumor progression and metastasis. Cell Rep. 2021, 37, 110056.
  33. Jiang, S.Y.; Li, H.; Tang, J.J.; Wang, J.; Luo, J.; Liu, B.; Wang, J.K.; Shi, X.J.; Cui, H.W.; Tang, J.; et al. Discovery of a Potent HMG-CoA Reductase Degrader That Eliminates Statin-Induced Reductase Accumulation and Lowers Cholesterol. Nat. Commun. 2018, 9, 5138.
  34. Boucher, Y.; Kamekura, M.; Doolittle, W.F. Origins and evolution of isoprenoid lipid biosynthesis in archaea. Mol. Microbiol. 2004, 52, 515–527.
  35. Clizbe, D.B.; Owens, M.L.; Masuda, K.R.; Shackelford, J.E.; Krisans, S.K. IDI2, a second isopentenyl diphosphate isomerase in mammals. J. Biol. Chem. 2007, 282, 6668–6676.
  36. Chen, Z.; Zhou, X.; Zhou, X.; Tang, Y.; Lu, M.; Zhao, J.; Tian, C.; Wu, M.; Liu, Y.; Prochownik, E.V.; et al. Phosphomevalonate Kinase Controls β-Catenin Signaling via the Metabolite 5-Diphosphomevalonate. Adv. Sci. 2023, 10, e2204909.
  37. Seshacharyulu, P.; Rachagani, S.; Muniyan, S.; Siddiqui, J.A.; Cruz, E.; Sharma, S.; Krishnan, R.; Killips, B.J.; Sheinin, Y.; Lele, S.M.; et al. FDPS cooperates with PTEN loss to promote prostate cancer progression through modulation of small GTPases/AKT axis. Oncogene 2019, 38, 5265–5280.
  38. Schmid, R.M. HMG-CoA reductase inhibitors for the treatment of pancreatic cancer. Gastroenterology 2002, 122, 565–567.
  39. Van de Donk, N.W.; Kamphuis, M.M.; van Kessel, B.; Lokhorst, H.M.; Bloem, A.C. Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels. Blood 2003, 102, 3354–3362.
  40. Waters, A.M.; Der, C.J. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb. Perspect. Med. 2018, 8, a031435.
  41. Kemp, S.B.; Cheng, N.; Markosyan, N.; Sor, R.; Kim, I.K.; Hallin, J.; Shoush, J.; Quinones, L.; Brown, N.V.; Bassett, J.B.; et al. Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer. Cancer Discov. 2023, 13, 298–311.
  42. Kazi, A.; Xiang, S.; Yang, H.; Chen, L.; Kennedy, P.; Ayaz, M.; Fletcher, S.; Cummings, C.; Lawrence, H.R.; Beato, F.; et al. Dual Farnesyl and Geranylgeranyl Transferase Inhibitor Thwarts Mutant KRAS-Driven Patient-Derived Pancreatic Tumors. Clin. Cancer Res. 2019, 25, 5984–5996.
  43. Biancur, D.E.; Kapner, K.S.; Yamamoto, K.; Banh, R.S.; Neggers, J.E.; Sohn, A.S.W.; Wu, W.; Manguso, R.T.; Brown, A.; Root, D.E.; et al. Functional Genomics Identifies Metabolic Vulnerabilities in Pancreatic Cancer. Cell Metab. 2021, 33, 199–210.e8.
  44. Jiang, H.; Tang, E.; Chen, Y.; Liu, H.; Zhao, Y.; Lin, M.; He, L. Squalene synthase predicts poor prognosis in stage I–III colon adenocarcinoma and synergizes squalene epoxidase to promote tumor progression. Cancer Sci. 2022, 113, 971–985.
  45. Bai, R.; Rebelo, A.; Kleeff, J.; Sunami, Y. Identification of prognostic lipid droplet-associated genes in pancreatic cancer patients via bioinformatics analysis. Lipids Health Dis. 2021, 20, 58.
  46. Wang, S.; Dong, L.; Ma, L.; Yang, S.; Zheng, Y.; Zhang, J.; Wu, C.; Zhao, Y.; Hou, Y.; Li, H.; et al. SQLE facilitates the pancreatic cancer progression via the lncRNA-TTN-AS1/miR-133b/SQLE axis. J. Cell. Mol. Med. 2022, 26, 3636–3647.
  47. Xu, R.; Song, J.; Ruze, R.; Chen, Y.; Yin, X.; Wang, C.; Zhao, Y. SQLE promotes pancreatic cancer growth by attenuating ER stress and activating lipid rafts-regulated Src/PI3K/Akt signaling pathway. Cell Death Dis. 2023, 14, 497.
  48. Zhao, F.; Huang, Y.; Zhang, Y.; Li, X.; Chen, K.; Long, Y.; Li, F.; Ma, X. SQLE inhibition suppresses the development of pancreatic ductal adenocarcinoma and enhances its sensitivity to chemotherapeutic agents in vitro. Mol. Biol. Rep. 2022, 49, 6613–6621.
  49. Sun, H.; Li, L.; Li, W.; Yang, F.; Zhang, Z.; Liu, Z.; Du, W. p53 transcriptionally regulates SQLE to repress cholesterol synthesis and tumor growth. EMBO Rep. 2021, 22, e52537.
  50. Liu, D.; Wong, C.C.; Fu, L.; Chen, H.; Zhao, L.; Li, C.; Zhou, Y.; Zhang, Y.; Xu, W.; Yang, Y.; et al. Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target. Sci. Transl. Med. 2018, 10, eaap9840.
  51. Li, C.; Wang, Y.; Liu, D.; Wong, C.C.; Coker, O.O.; Zhang, X.; Liu, C.; Zhou, Y.; Liu, Y.; Kang, W.; et al. Squalene epoxidase drives cancer cell proliferation and promotes gut dysbiosis to accelerate colorectal carcinogenesis. Gut 2022, 71, 2253–2265.
  52. Jun, S.Y.; Brown, A.J.; Chua, N.K.; Yoon, J.Y.; Lee, J.J.; Yang, J.O.; Jang, I.; Jeon, S.J.; Choi, T.I.; Kim, C.H.; et al. Reduction of Squalene Epoxidase by Cholesterol Accumulation Accelerates Colorectal Cancer Progression and Metastasis. Gastroenterology 2021, 160, 1194–1207.e28.
  53. Lasunción, M.A.; Martín-Sánchez, C.; Canfrán-Duque, A.; Busto, R. Post-lanosterol biosynthesis of cholesterol and cancer. Curr. Opin. Pharmacol. 2012, 12, 717–723.
  54. Nguyen, T.P.; Wang, W.; Sternisha, A.C.; Corley, C.D.; Wang, H.L.; Wang, X.; Ortiz, F.; Lim, S.K.; Abdullah, K.G.; Parada, L.F.; et al. Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by inducing 24(S),25-epoxycholesterol production. Cell Chem. Biol. 2023, 30, 214–229.e18.
  55. Wong, C.C.; Wu, J.L.; Ji, F.; Kang, W.; Bian, X.; Chen, H.; Chan, L.S.; Luk, S.T.Y.; Tong, S.; Xu, J.; et al. The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer. Nat. Commun. 2022, 13, 3971.
  56. Li, J.; Gu, D.; Lee, S.S.; Song, B.; Bandyopadhyay, S.; Chen, S.; Konieczny, S.F.; Ratliff, T.L.; Liu, X.; Xie, J.; et al. Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer. Oncogene 2016, 35, 6378–6388.
  57. Yang, W.; Bai, Y.; Xiong, Y.; Zhang, J.; Chen, S.; Zheng, X.; Meng, X.; Li, L.; Wang, J.; Xu, C.; et al. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism. Nature 2016, 531, 651–655.
  58. Hao, M.; Hou, S.; Li, W.; Li, K.; Xue, L.; Hu, Q.; Zhu, L.; Chen, Y.; Sun, H.; Ju, C.; et al. Combination of metabolic intervention and T cell therapy enhances solid tumor immunotherapy. Sci. Transl. Med. 2020, 12, eaaz6667.
  59. Wang, Z.; Wang, M.; Zhang, M.; Xu, K.; Zhang, X.; Xie, Y.; Zhang, Y.; Chang, C.; Li, X.; Sun, A.; et al. High-affinity SOAT1 ligands remodeled cholesterol metabolism program to inhibit tumor growth. BMC Med. 2022, 20, 292.
  60. Liu, C.; Chen, J.; Chen, H.; Zhang, T.; He, D.; Luo, Q.; Chi, J.; Hong, Z.; Liao, Y.; Zhang, S.; et al. PCSK9 Inhibition: From Current Advances to Evolving Future. Cells 2022, 11, 2972.
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