Fatty acid metabolism and prostate cancer – Following the science to where it leads us

By Cade J Gosser & Houjian Cai; Fatty acid metabolism is notoriously dys-regulated in prostate cancer. Our study offers a potential therapeutic target of ACSL1 for treatment of prostate cancer. This post describes how our studies direct us the way to find the target.

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Prostate cancer (PCa) accounts for the second highest number of cancer deaths among males in North America. I got lucky to start the research by the support of a fellowship from the Department of Defense focusing on the role of Src family kinases (SFKs) in PCa. SFK research has been conducted for decades including tremendous work by two Nobel laureates, and PubMed-searching Src kinase returned thousands of hits. Therefore, finding a unique niche for the novelty of a career was very difficult. However, by comparing oncogenic potential of Src, Fyn, and Lyn kinases in prostate cancer progression, we discovered that the N-terminals of SFKs and their modifications, myristoylation and palmitoylation, play an essential role in tumorigenic potentials (1). These lipid modifications were known to be involved in tethering SFKs to the cytoplasmic membrane (2). Moreover, there was growing evidence suggesting that myristoylation regulates Src kinase stability and activity (3). “Let science lead the way of your study” as my mentors always said. After my lab was established and further supported by the DOD and NIH, we began to explore the N-terminal myristoylation of SFKs in PCa (4). This research topic led us to discover the regulation of N-myristoyltransferase 1 (NMT1) on Src kinase along with inhibitors of NMT1 (5)

 Following the success of the above study in inhibiting myristoylation of Src kinase as a potential strategy for treatment of PCa, the science led us to study long-chain acyl CoA synthetase (ACSL) enzymes in terms of their role in providing fatty acyl-CoAs, including myristoyl-CoA, as a substrate for Src myristoylation and fatty acid metabolism. ACSLs are comprised of five family members: ACSL1, 3, 4, 5, and 6. While ACSL3 and ACSL4 levels are regulated by androgen receptor in PCa as reported in other research (6), we aim to investigate the ACSL1-mediated fatty acid metabolism in this study (7).

We first systematically examined the association of fatty acyl-CoAs levels and ACSLs mRNA expression levels in a variety of normal and cancer cells. Our data revealed that ACSL1 regulates production of various lengths of acyl-CoAs in cancer cells including 14:0-, 16:0-, 18:0-, 18:1-, and 18:2-CoA. Additionally, expression levels of ACSL1 were elevated in PCa based on the analysis of a prostate tumor tissue array, suggesting that ACSL1 is a prime target for cancer treatment because of its important role in the fatty acyl-CoAs biosynthesis. We further reported that knockdown of ACSL1 inhibited the growth of prostate xenograft tumors and prevented G1 phase development, as seen by varied expression of cell cycle protein markers.

As it is well-documented, fatty acid metabolism is notoriously dysregulated in PCa. We predict that ACSL1 will be a potential therapeutic target because of its essential role in directing internal/exogenous dietary fatty acid metabolism for ATP production, lipid biosynthesis, and prostate cell proliferation. We hope that the science will lead us further to explore the unknown world of fatty acid metabolism for treatment of PCa.

 References

  1. Cai H, Smith DA, Memarzadeh S, Lowell CA, Cooper JA, Witte ON. Differential transformation capacity of Src family kinases during the initiation of prostate cancer. Proc Natl Acad Sci U S A. 2011;108(16):6579-84.
  2. Resh MD. Myristylation and palmitylation of Src family members: the fats of the matter. Cell. 1994;76(3):411-3.
  3. Patwardhan P, Resh MD. Myristoylation and membrane binding regulate c-Src stability and kinase activity. Molecular and cellular biology. 2010;30(17):4094-107.
  4. Kim S, Yang X, Li Q, Wu M, Costyn L, Beharry Z, et al. Myristoylation of Src kinase mediates Src-induced and high-fat diet-accelerated prostate tumor progression in mice. J Biol Chem. 2017;292(45):18422-33.
  5. Kim S, Alsaidan OA, Goodwin O, Li Q, Sulejmani E, Han Z, et al. Blocking myristoylation of Src inhibits its kinase activity and suppresses prostate cancer progression. Cancer Res. 2017.
  6. Ma Y, Zhang X, Alsaidan OA, Yang X, Sulejmani E, Zha J, et al. Long-Chain Acyl-CoA Synthetase 4-Mediated Fatty Acid Metabolism Sustains Androgen Receptor Pathway-Independent Prostate Cancer. Mol Cancer Res. 2021;19(1):124-35.
  7. Ma Y, Zha J, Yang X, Li Q, Zhang Q, Yin A, et al. Long-chain fatty acyl-CoA synthetase 1 promotes prostate cancer progression by elevation of lipogenesis and fatty acid beta-oxidation. Oncogene. 2021.

Houjian Cai

Associate Professor, University of Georgia