Fatty acids metabolism is rewired significantly in prostate cancer (PCa). Although PCa can be treated with hormone therapy, after prolonged treatment, castration-resistant prostate cancer (CRPC) can develop and can lead to increased mortality. We aimed to summarize the reprogramming of FA metabolism in PCa, especially in advanced PCa. Both whole-body FA metabolism in PCa patients and cellular FA metabolism play important roles in PCa origination and development. FA metabolism may provide potential candidate targets for the treatment or diagnosis of PCa.

In the whole-body FA metabolism, obesity has been reported to correlate with higher risk for biochemical recurrence after radical prostatectomy and for PCa-specific mortality. This effect may be due to obesity-related alterations of serum cytokines and some proliferative hormones, such as increased serum estrogen, insulin, insulin-like growth factor-1 and leptin, and reduced testosterone. In our research, we also found the serum lipid level changed a lot between PCa patients and individuals without PCa. The serum lipid concentration contributes to the PCa diagnosis, especially in the patients with PSA 4-10 ng/ml. Moreover, the intake of food and nutrients also strongly affect the incidence and progress of PCa. Though there are still controversies among the nutrients effect on PCa, high fat diet is reported to induce the development of PCa progress.

As to the cellular FA metabolism, there are mainly four processes: FA uptake, FA de novo synthesis, FA elongation and FA oxidation.

1. FA uptake.

FA concentrations are significantly upregulated in PCa tissues. This can be confirmed by magnetic resonance imaging (MRI), which technique has been used to demonstrate that lipids are relatively abundant in PCa tissues. PCa tissues are not sensitive to analysis with 18F-glucose-positron emission tomography or computed tomography because of the limited glucose uptake and level of glycolysis. Glycolysis does increase with PCa development, and this technique becomes more sensitive in advanced PCa tissue. However, as lipid concentrations remain high in PCa tissues, other techniques using fatty acids are better candidates for detection and diagnosis. Though there is close relationship between FA uptake and PCa progression, different types of FA have individual effects. The increased uptake of oleic acid and palmitic acid tend to increase cell proliferation, for instance. However, excess palmitate causes oxygen stress, leading to apoptosis, and this effect can be prevented by pre-treatment with oleate or through triacylglycerol synthesis. However, in our previous study, we did not find that neuroendocrine prostate cancer (NEPC) cells benefit from the uptake of palmitate and oleic acid while arachidonic acid, a kind of PUFA, contributed to the activation of the AKT–mTOR pathway, inducing the neuroendocrine switch and enzalutamide resistance.

2. FA de novo synthesis.

To use FA as an energy source, normal prostatic cells rely mostly on circulating lipids. PCa is marked by increasing rates of de novo FA synthesis. The key enzyme for this process is fatty acid synthase (FASN), which catalyzes the synthesis of palmitate from malonyl-CoA and acetyl-CoA, using metabolites that originate mainly from glucose or glutamine. Palmitate generation is followed by desaturation and elongation for the production of more types of FA. According to our studies of microarrays from prostate cancer patients, FASN is upregulated in PCa tissues and is increased with the elevation of Gleason’s Score and clinical stages. In prostate cancer, AR is critical for initiation and development. As a transcriptional factor, AR has been reported to activate sterol regulatory element-binding proteins (SREBPs), which play a central role in FA metabolism, especially in FASN expression. These connections can also explain why FASN and SREBPs are significantly increased in PCa tissues and cells, especially in metastatic CRPC cases. The upregulation of FA generation contributes to the architecture of the cellular membrane. Moreover, it also contributes to the enhancement of cell signaling pathways, including the activation of the AKT–mTOR pathway and epigenetic regulation of k-RAS and WNT-1.

3. FA Elongation.

Fatty acid elongation is another critical pathway in FAs formation. They have multiple functions which can influence the cellular fate. Overall, as is generally understood, w-6 PUFA tend to accelerate inflammation, cancer cell proliferation, and metastasis, whereas, w-3 typically oppose these effects. Members of the elongation of very long chain fatty acids (ELOVL) protein family are key enzymes involved in the FA elongation process. In our research, we reported that ELOVL5, as one of the ELOVL members, is the key enzyme for PUFA production. Moreover, FA elongation is enhanced after prolonged androgen deprivation therapy and in advanced PCa, including neuroendocrine PCa (NEPC). With additional arachidonic Acid (AA), one of the main PUFA, in the cell culture medium, prostate cancer cell lines present more enzalutamide resistance. When ELOVL5 is overexpressed, PCa cell lines shows elevated enzalutamide resistance, similar to the effect of adding extra AA to the growth medium. However, with ELOVL5 downregulation, cells are more sensitive to hormone therapy. This effect is through the lipid raft-mTOR-AKT pathway, which is significant for CRPC treatment. ELOVL5 can also be significantly regulated by SREBP1-c and regulates the mTORC2-Akt-FOXO1 pathway by controlling hepatic cis-vaccenic acid synthesis in diet-induced obese mice. In this way, the inhibition of long chain FA uptake might be a potential treatment for CRPC and to increase the hormone therapy sensitivity.

4. Fatty Acid Oxidation
   FA oxidation is associated with energy harvesting. However, fatty acid reprogramming should also be placed in a different context: as a critical gatekeeper that is regulated by oncogenic signals to drive cancer growth and development. In PCa cells, FA oxidation is increased, and the key enzyme, carnitine palmitoyltransferase 1 (CPT1)—which catalyzes the transfer of long-chain FA into the mitochondria for further oxidation—is upregulated. The dominant metabolic role of FA oxidation, rather than glycolysis, has the potential to fuel PCa growth and to be the basis for imaging-based diagnoses and targeted treatment of PCa. Findings have also investigated that carnitine system could regulate the metabolic flexibility of cancer cells, which plays a fundamental role in switching between the glucose and FA metabolism. The use of FA, either for energy or for nuclear transportation, is a critical determinant of cellular fate. However, in our previous research, we did not find that FA oxidation was enhanced in CRPC-NEPC cell lines. Instead, the source of oxidation mainly depends on the FA present in the medium. LNCaP/AR-shp53/shRB PCa cells—which are NE-like PCa cells—are less sensitive to FA depletion than LNCaP/AR cells are, which indicates that
   NE-like PCa cells may depend less on FA oxidation. The significance of FA metabolism can be probed with etomoxir, the most widely used inhibitor of CPT1, and hence, block the carnitine shuttle. This may be caused by the increased use of glutamine as fuel in NEPC cells, which is caused by the decreased expression of kidney-type glutaminase (KGA) and upregulation of glutaminase 1 in hormone therapy resistant and NEPC cells.

This entry is adapted from the peer-reviewed paper 10.3390/metabo11110765