Heat Shock Proteins in Colorectal Carcinoma: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Jibran Sualeh Muhammad.

Cancer cells can reprogram their metabolic activities and undergo uncontrolled proliferation by utilizing the power of heat shock proteins (HSPs). HSPs are highly conserved chaperones that facilitate the folding of intracellular proteins under stress. Constitutively, HSPs are expressed at low levels, but their expression upregulates in response to a wide variety of insults, including anticancer drugs, allowing cancer cells to develop chemoresistance.

  • heat shock proteins
  • colorectal carcinoma
  • Theranostics

1. Targeting HSPs for CRC Therapy

Increasing evidence has suggested HSPs as novel therapeutic targets for cancer therapy [74][1]. Because of their abnormal expression in cancer cells, the cells can produce proteins and thrive in the extremely harsh conditions of the cancer microenvironment [75][2]; thus, it is unsurprising that targeting HSPs with different inhibitors may overcome their oncogenic properties and exert a potent anticancer effect. Indeed, there has been increasing interest in identifying and developing inhibitors to target individual HSPs, attenuate their function, and inhibit cancer progression (Table 1).
Table 1. Chemotherapies targeting HSPs inhibitors in CRC.
HSPs HSP Inhibitors Source Mechanism of Action
HSP90 17-AAG Geldanamycin derivative Target the ATP binding pocket
DDO-5936 Small-molecule inhibitor Inhibits PPI with CdC37
12c Chemotherapies with resorcinol Inhibits target-independent activation
HSP70 EGCG Small-molecule inhibitor Promotes Grp78 dimerization
Quercetin Flavonoid group of polyphenols Reduces HSP70 expression
Kahweol Small molecule inhibitor Reduces HSP70 expression
Cantharidin Small-molecule inhibitor Inhibits HSF1
Fisetin Dietary flavonoid Inhibits HSF1
AP-4-139B Small-molecule inhibitor Target mitochondrial cancer cell
AT7519 Small-molecule inhibitor Inhibits CDK9
PES Small-molecule inhibitor Interaction with SBD of HSP70
Apoptozole Small-molecule inhibitor Target the ATP binding pocket
MKT-077 Cationic rhodacyanine Target the ATP binding pocket
A8 aptamer Aptamers Binds to the extracellular domain of HSP70
cmHsp70 Monoclonal antibody-based Induces ADCC
Pluronic Sensitizing agent Reduces HSP70 expression
Hexachlorophene Antimicrobial compound and disinfectant Interaction with SBD of GRP78
DHA Polyunsaturated fatty acids MEK/ERK pathway activation
sHSP Quercetin Flavonoid group of polyphenols Binds to HSP27 and inhibits its activity
YangZheng XiaoJi Chinese anticancer compound Inhibits HSP27 localization with caspases 9
Ova curcumin small-molecule inhibitor anti-CSC effect on CRC
DTNQ-Pro Naturally according quinone-based pentacyclic derivative HSP70 redistribution
Cetuximab monoclonal antibody-based Inhibits JAK/STAT signaling pathway
OGX427 ASO Abolished the formation of GJIC

1.1. HSP90 Inhibitors

HSP90 inhibitors are the most extensively studied HSP inhibitors for cancer therapy [76][3]. HSP90 plays a significant role in cell proliferation, differentiation, and metastasis by interacting with and stabilizing major oncogenes to promote abnormal cancer cell growth [21][4]. Although the HSP90 family has four members with different client protein targets, they share the same structure. Because they are ATP-dependent chaperones on their N-terminal domains, they have ATP binding pockets. By targeting this domain, more than one HSP90 member can be inhibited using a single HSP90 inhibitor known as a pan-HSP90 inhibitor [77][5]. The first-in-class HSP90α inhibitor is 17-allylamino-17-demethoxygeldanamycin (17-AAG)—a geldanamycin derivative that specifically targets the ATP binding pocket of HSP90. 17-AAG inhibits the ATPase activity of HSP90 and consequently promotes degradation of HSP90 through proteasome mechanisms [78][6]. Following 17-AAG treatment, CRC cells were arrested at G2 due to a reduction in cyclin B1 levels.
Furthermore, 17-AAG downregulates STAT3 to induce apoptosis in CRC cells [78][6]. To date, more than 18 different HSP90 inhibitors have reached the clinical trial stage. Unfortunately, none have had sufficient efficacy to earn FDA approval [77][5] due to their elevated toxicity, since numerous HSP90 client proteins play an essential role in normal body development [79][7]. The research community is now looking for an alternative way to specifically target the oncogenic client proteins of HSP90, which may be achieved by targeting its protein-protein interaction (PPI) with other co-chaperones [79][7]. One example is targeting CdC37, which is a co-chaperone that explicitly allows for HSP90-kinase interactions. Instead of broadly targeting the ATPase activity of HSP90, targeting the HSP90-Cdc37 PPI would inhibit kinase maturation and allow for safe and specific anticancer treatment [79][7]. Different compounds are being tested for this interaction, showing promising results in both in vitro and in vivo experiments [79][7].
One of these compounds is the small-molecule inhibitor DDO-5936 [80][8]. DDO-5936 bound to Glu47 residue of HSP90 and disrupted the PPI with Cdc37 with subsequent inhibition of kinase client proteins of HSP90 in a CRC cell line. CRC cell proliferation was inhibited due to subsequent degradation of cyclin-dependent kinase 4 (Cdk4). Another limitation of HSP90 inhibitors is their export by ATP-binding cassette (ABC) transporters, making cancer cells resistant to these inhibitors [13][9]. An example of ABC transporters is P-glycoprotein (P-gp), which pumps foreign molecules outside cells to cause multidrug resistance (MDR); thus, it seems that dual-activity drugs targeting both HSP90 and P-gp have potent activity as anti-CRC therapies. For this purpose, eleven HSP90 inhibitors were tested to inhibit cancer growth and MDR caused by P-gp, and 3 out of the 11 tested compounds succeeded in inhibiting P-gp overexpression and MDR together with HSP90 in CRC cells. These compounds are potential anticancer treatments for overexpressing P-gp in CRC [13][9].
However, there are other mechanisms by which cancer cells can become resistant to HSP90 inhibitors, such as the target-independent activation of downstream proteins. This activation is mainly caused by mutations that change the target expression and activate an alternative pathway to produce the target [13][9]; therefore, HSP90 inhibitors potency may be improved when combined with other standard chemotherapies [81][10]. Following this suggestion, Wu et al. identified a series of drugs known as luoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides using a combination of different chemotherapies with resorcinol and HSP90 inhibitors [82][11]. One of these compounds, 12c, was remarkably active in CRC cell lines, proving the role of this novel HSP90 inhibitor in CRC treatment. In another study, Moradi et al. combined 17-AAG with irradiation (Ir) and gold nanoparticle (GNP) therapies, revealing a potential anticancer treatment by inhibiting cell proliferation and the induction of apoptosis for CRC cells, which further proved the role of combination therapy [15][12]. It has also been reported that HSP90 inhibitors seem to have contradictory effects depending on the molecular subtype of CRC (CMS) [81][10], demonstrating a need for prior identification of patient CMS to improve the effectiveness of HSP90 inhibitors when combined with different administered chemotherapies. This combination may overcome resistance to HSP90 inhibitors and offer improved opportunities for CRC treatment.

1.2. HSP70 Inhibitors

Unlike normal cells, HSP70 is overexpressed in cancer cells even under stressful conditions [6][13]; therefore, several anticancer therapies are now being designed to target HSP70 activity. Inhibitors of HSP70 are categorized according to three main groups: small-molecule inhibitors, peptide aptamers, and antibody-based therapy [2][14]. Several small-molecule inhibitors have been identified that target HSP70 activity in CRC. One of which is the natural compound epigallocatechin-3-gallate (EGCG), which has shown a promising antitumor effect on CRC in vitro and in vivo experiments. EGCG specifically targets the ATPase domain of Grp78 to promote its dimerization and, consequently, its inactivation [14][15]. Other small-molecule inhibitors that target HSP70 are quercetin and Kahweol [83,84][16][17]. CRC cells treated with either of these inhibitors exhibited reduced expression of HSP70 and a significant reduction in tumor growth. HSP70 can also be inhibited indirectly by targeting the primary regulator of the heat shock response—heat shock transcription factor 1 (HSF1) [14,85][15][18]. The anticancer molecule cantharidin significantly inhibited HSF1, its downstream HSP70 molecules, and its co-chaperone B-cell lymphoma 2 (Bcl-2)-associated anthanogene (BAG3). This inhibition was accompanied by increased cancer cell death [14][15]. Additionally, fisetin—a dietary flavonoid with anticancer potency—has been reported to promote the apoptosis of CRC cells by inhibiting HSF1 interaction with HSP70, thereby inhibiting the latter’s activity [85][18]. A novel HSP70 inhibitor (AP-4-139B) was recently identified that targets mitochondria of cancer cells but not of the normal cells, which proved to have inhibition potency and reduced toxicity [66][19]. Furthermore, there is increasing evidence of the upregulation of HSP70 expression and resistance to the HSP90 inhibitor, onalespib. Considering this, the efficacy of onalespib was tested in combination with the HSP70 inhibitor AT7519. AT7519 is a small-molecule inhibitor of CDK9—a catalytic subunit of the positive transcription elongation factor (P-TEFb)—that enhances the elongation of the HSP70 transcript. Using this combination resulted in promising preliminary clinical activity [86][20].
Furthermore, 2-Phenylethynesulfonamide (PES), also known as pifithrin-µ, is a well-known inhibitor of HSP70 that interacts explicitly with its substrate-binding domain (SBD) [87][21]. HSP70 binds to its client protein through a unique amino acid motif present on its SBD. PES competes with HSP70 client proteins and co-chaperones on SBD, thereby disrupting the folding of essential proteins required by cancer cells. PES combined with oxaliplatin chemotherapy showed potent anticancer effects on CRC cells [87][21]. Indeed, this combination was more effective with minimal side effects than when the elements were introduced separately [2][14]. Apoptozole is another recently identified small molecule that targets HSP70, specifically in CRC cells [14][15]. Apoptozole binds to the ATP binding pocket of HSP70 to inhibit its ATPase activity. Apoptozole has a potential anticancer effect on CRC cells both in vitro and in vivo. Lastly, MKT-077a cationic rhodacyanine derivative—has been reported to target the ATPase activity of HSP70 in CRC cells and was the first drug to reach the clinical trial stage [2][14]. However, the trial was terminated due to high drug toxicity. Another recently discovered antitumor alkaloid drug derived from the Liliaceae plant has been shown to inhibit mortalin-2 (mot-2) indirectly through the upregulation of UBX Domain Protein 2A (UBXN2A), which, in turns, inhibits mortalin [88][22].
Aptamers are the second group of HSP70 inhibitors that bind to different domains of HSP70 [2][14]. So far, few studies have considered HSP70 inhibitor aptamers that target CRC. Of the different aptamers tested, the A8 aptamer could bind to the extracellular domain of HSP70 and inhibit its oncogenic activity in a CT26 mouse colon cancer model [89][23].
The third group consists of monoclonal antibody-based inhibitors, including cmHsp70, which can bind to HSP70 on the membrane of CT26 cells by recognizing the specific amino acid sequence TKDNNLLGRFELSG (TDK). This binding induced antibody-dependent cellular cytotoxicity (ADCC) on bound cancer cells, reduced the tumor mass and increased OS in the CT26 model [90][24]. Unlike other commercial antibodies, cmHsp70.1 can bind and detect the expression of HSP70 in living tumor cells. However, A8 is favored over cmHSP70.1 because of its greater stability, solubility, and manufacturing simplicity [89][23].
Other HSP70 inhibitors have recently been identified that are not a member of any of the previous groups. One example is Pluronic® which is a non-toxic sensitizing agent for the hyperthermia treatment of cancer [91][25]. Pluronic® is a mixed copolymer of hydrophobic and hydrophilic polymers that have been shown to inhibit HSP70 expression in CRC cells under hyperthermia; thus, it seems that Pluronic® enhances the toxicity of thermal treatment for CRC cells due to the inhibition of HSP70 activity [91][25]. Additionally, hexachlorophene—an antimicrobial compound and disinfectant—has been reported to target a specific member of HSP70 (GRP78) by binding to its SBD and inhibiting substrate binding [92,93][26][27]. Hexachlorophene treatment of CRC cells has been found to induce autophagy and increase apoptosis due to GRP78 inhibition.
Furthermore, n-3 PUFA docosahexaenoic acid (DHA)—a potent anticancer therapy—explicitly targetsGRP78. Previously, it was reported that DHA treatment induced apoptosis and reduced tumor growth in CRC [94,95][28][29]; however, few studies have investigated the DHA anticancer mechanism. It was recently reported that DHA reduced MEK/ERK pathway activation by inhibiting ERK phosphorylation. This inhibition caused the downregulation of GRP78 expression and altered its original location in the endoplasmic reticulum (ER) [94][28]. Together, these inhibitors and their role in CRC treatment show the need to understand the HSP70 oncogenic mechanism in CRC progression.

1.3. sHSP Inhibitors

sHSPs are ubiquitously expressed in different organisms, playing a significant role in cellular proliferation, differentiation, and degradation. sHSPs are not only involved in protein refolding but also play a role in attenuating the aggregation of proteins under stressful conditions [96][30]; therefore, they have been proposed for different types of cancer progression, including CRC, and different inhibitors are being tested for their potent anticancer effects [61][31]. Unlike other HSPs, sHSPs do not have ATP binding pockets to perform their function in an ATP-independent manner. Otherwise, they have three main domains; a structured α-crystalline domain (ACD), an amino-terminal region (NTR), and a carboxy-terminal region (CTR) [96][30]. In recent years, numerous anticancer drugs have been designed to specifically target different domains of sHSPs. These sHSP inhibitors are categorized according to four major groups: small-molecule inhibitors, aptamers, monoclonal antibodies, and antisense oligonucleotides (ASO) [2][14].
Different small-molecule inhibitors are being tested against HSP27. Quercetin—a member of the flavonoid group of polyphenols—has exhibited potent anticancer activity against primary colon cancer cells by binding to HSP27 and inhibiting its activity [97][32]. Nevertheless, no current clinical trials are testing quercetin’s effectiveness on humans [2][14]. In addition, YangZheng XiaoJi—a Chinese anticancer compound—can also inhibit HSP27 phosphorylation in different cancers, including CRC [98][33], by inhibiting HSP27 localization with caspase_9; the HSP27 function is inhibited in cancer cells through the inhibition of phosphorylation or its colocalization with caspase-9 [98][33]. Additionally, ovatodiolide (Ova) is a small-molecule inhibitor isolated from Anisomeles indica that has a potent anticancer stem cell (anti-CSC) effect on different cancers, including breast cancer and CRC [99,100][34][35]. In breast cancer cells, Ova reduced HSP27 expression to suppress tumor growth [100][35]. Although Ova has an anti-CSC effect on CRC cells, this effect was identified with a different mechanism in breast cancer [99][34]. Further studies are recommended to study its effect on HSP27 in CRC cells. Another naturally occurring anticancer agent is curcumin, the effect of which on CRC cells was tested after silencing HSP27. Interestingly, CRC cells lacking HSP27 exhibited resistance to curcumin treatment and, thus, reduced apoptosis; therefore, this study suggested that HSP27 is a potential target for curcumin in CRC [101][36]. A quinone-based pentacyclic derivative (3S,3′R) spiro[(hexahydropyrrolo[1,2-a]pyrazine-1,4-dione)-6,3′-(2′,3′-dihydrothieno[2,3-b]naphtho-4′,9′-dione)] (DTNQ-Pro) is a novel synthetic anti-cancer agent with broad-spectrum activity on different types of cancers, including CRC. Unlike other therapies, DTNQ-Pro did not reduce HSP27 expression, but caused its redistribution inside cancer cells to the cytoplasm compared to the perinuclear HSP27 in control cells [102][37].
The second inhibition approach focuses on monoclonal antibodies (mainly cetuximab), which block epidermal growth factor receptor (EGFR) activity [103][38]. Cetuximab sensitizes CRC cells to CPT-11—a chemotherapy drug—by suppressing HSP27 activity by targeting the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. Interestingly, cetuximab could suppress HSP27 even in RAS- or BRAF-mutated cells considered resistant to cetuximab therapy. These findings may offer novel strategies for overcoming resistance to cetuximab in RAS- and BRAF-mutated CRC cells.
The third approach utilizes aptamers that can bind to HSP27 and inhibit its dimerization. The most well-known aptamers are PA11 and PA50, which bind to HSP27 oligomers and inhibit their tumorigenic effect [96][30]. The effect of these aptamers has only been studied in cancers other than CRC, including prostate cancer, small cell lung cancer (SCLC), and head and neck squamous cell carcinoma [2,96][14][30]. The effect of aptamer on CRC requires further study.
The final approach that was recently identified involves the antisense oligonucleotide (ASO). The ASO OGX427 has been shown to inhibit the mRNA expression of HSP27 [96][30]. ASO approaches have been extensively studied in patients with prostate, bladder, ovarian, breast, and non-small cell lung cancers [96][30]. In CRC, OGX427 activity was tested on the SW480 cell line to study the inhibition of gap junction intercellular communication (GJIC) formation mediated by HSP27. Notably, inhibition of HSP27 by OGX427 abolished the formation of GJIC and therefore altered the interaction of the CRC cell line with endothelial cells [104][39].

1.4. HSP60 Inhibitors

Targeting various HSPs for cancer chemotherapy has recently gained attention due to their significant role in CRC progression; however, few studies have targeted HSP60 activity and its co-chaperone HSP10 for CRC treatment due to their controversial role in different cancers. Nevertheless, there are two resources for HSP60 inhibitors—natural and synthetic—and, mechanistically, these inhibitors interact with ATP binding pockets or a specific cysteine residue in Hsp60 [105][40]. Various natural inhibitor compounds were tested against HSP60, including mizoribine, epolactaene, and myrtucommulone A (MC). Mizoribine was reported to inhibit the ATPase activity of HSP60, while epolactaene bound to the Cys442 residue of HSP60 to inhibit its activity [105][40]. Unfortunately, few synthetic compounds were able to target HSP60 activity, one of which was o-carboranylphenoxyacetanilide, but none of the above-mentioned inhibitors were tested on CRC cell lines. Overall, these studies have provided a better understanding of these inhibitors’ bioactivity and have therefore paved the way for testing on CRC.
Recently, another 24 different inhibitors were tested against HSP60 activity in CRC and showed significant inhibition of CRC cells compared to normal cells. Interestingly, the effect on CRC cell viability of those inhibitors was associated with the inhibition of expression of HSP60, thus, indicating that HSP60 might be a target for these inhibitors [106][41].

1.5. HSP110 Inhibitors

Only limited studies have focused on the role of HSP110 in CRC, and little research has targeted its activity. Gozzi and his colleagues identified two abiotic foldamers, 33 and 52, using chemical library screening to inhibit HSP110 functioning by targeting its NBD. These inhibitors were able to reduce CRC cell growth, as confirmed by an in vivo model. This study will open opportunities for discovering more molecules to target HSP110 for CRC treatment [107][42].

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