Role of Fat Transporter in Fat Metabolism and Cancer Development

Cancer Development

The term “cancer” refers to a wide range of conditions that all share one thing in common: They are all the result of healthy cells becoming malignant cells that grow and spread.

Medical professionals are simultaneously identifying independent risk factors for the disease to aid in cancer prevention. Despite decades of research, we still do not have a complete understanding of the complicated process by which cancer develops. The notion that cancer is not brought on by a single event is one of the most prevalent ones. Multiple sources claim that normal cells undergo a series of transformations into malignant ones. The cell cycle is an internal clock that governs how most healthy cells go through various stages of life. To begin the cell cycle, a single cell divides into two daughter cells. The cell cycle is controlled by signals from within and outside the cell.

When enough mutations occur in the many genes that regulate cell proliferation, cells can turn cancerous. The Cancer Genome Project’s study shows that the majority of cancer cells have 60 or more mutations. Finding which of these mutations causes a certain type of cancer is a challenge for medical experts. This approach is like looking for a needle in a haystack since the majority of the mutations discovered in these cells have little to no impact on how cancer develops.

Metabolism of Fats in Cancer

To meet energy demand and more biomolecules production cancer cells dysregulate their metabolism. Even within the same cancer type, the variation is very remarkable and significant in tumor cases. The altered tumor metabolism is also influenced by other factors, such as nutrition, eating habits, exercise, and the microbiota, in addition to the genetic changes that occur independently of the cell. 

Cancer cell growth, spread, and resistance to chemotherapeutics are affected by alterations in lipid metabolism. Only the liver and adipocytes can produce Fatty Acids (FA) and cholesterol on their own, while most adult tissues obtain these nutrients from the diet. Tumors are more dependent on externally supplied lipids because they can induce the de novo fatty acid and cholesterol synthesis. It is huge because it has been shown that the mevalonate pathway and additionally all over again lipogenesis-related catalysts can be focused on to stifle growth improvement [1]. ACLY uses citrate to make oxaloacetate (OAA) and AcCoA. The carboxylation of AcCoA-by-AcCoA carboxylases (ACC1/2) results in the formation of malonyl-CoA [2].

For de-novo synthesis of FA and cholesterol, fatty acid oxidation must take place inside the mitochondria and results in mobilization of the free fatty acids (FFAs) to the mitochondria. Tumor cells also face oxidative stress as compared to normal cells. As a result, apoptotic pathways are initiated due to ROS burden [3].

Lipid metabolism is frequently reprogrammed in cancer cells because these compounds are necessary for ATP production, cell division, and proliferation. Since tumor cells frequently up-regulate endogenous fatty acids and the fatty acid oxidation role in the tumor cells reprogramming are topics of significant interest. Because fatty acids are the precursors to the production of lipid signaling molecules, cancer cells dysregulate the metabolism of fatty acids for proliferation and metastasis.

Fat Transporters

The fatty acid molecule’s amphipathic nature, which includes a polar head group and a nonpolar chain, gives it the biophysical properties it needs to enter the cell membrane’s phospholipid bilayer. 

In the late 1900s, several researchers tried to find the mechanism of the transport of fatty acid and their binding partners. Now many proteins are known which are involved in the transport and binding of fatty acids [4].

Fatty acid Transporter Protein 1 (FATP1) is implicated in energy balance, thermogenesis, and insulin resistance, according to recent research. Both adipose and muscle contain this controlled fatty acid transporter. According to knockout mouse models, FATP5 is a bifunctional protein that is necessary for both the intake of hepatic fatty acids and the conjugation of bile acids [5].

Role of Fat Transporters in Cancer 

For effective FA transport across the plasma membrane, specialized transporters are required for exogenous FA absorption. CD36, which is also called as fatty acid translocase, is also known as SLC27, and fatty acid binding protein muscle (FABPm) are the three that are most well-known among them. All three of these proteins and genes are expressed more frequently in tumors. Particularly, high CD36 expression breast, ovarian, gastric, and prostate tumors have been identified as tumor types with poor prognoses. In extremely aggressive Pten prostate tumors, CD36 promotes high expression of Acyl CoA Synthetase (ACS) and Monoacylglycerol (MAGs) which are byproducts of FA oxidation. These progressions in lipid synthesis are additionally brought about by CD36 (FAO). Together, our findings demonstrate that CD36 is necessary for the metabolic interaction between tumor cells and their environment, eventually leading to tumor cells becoming more dependent on the absorption of exogenous lipids [6].

A superfamily of lipid-restricting proteins known as fatty acid binding protein (FABPs) is urgent for the retention, transport, and oxidation of unsaturated fats. Various functions which are played by these molecules are increase the intracellular transport uptake, plays role in the migration and proliferation of the tumor cells. Many cases of the cancer cells utilize them for the progression of the tumor cells. Growth of tumor cells is also promoted by the FABP3, which may be necessary for their proliferation. High FABP3 expression was significantly linked to a poor survival in patients with gastrointestinal stromal tumors, indicating its prognostic significance (GISTs).

Metabolism of fats is controlled by FABP4, but it is also crucial for apoptosis and proliferation of the tumor cells. The expression of FABP4 is regulated by fatty acids, PPAR agonists, and PPAR. Fats are important to the production and regulation of energy in living organisms. A significantly lower 5-year survival rate and a worse prognosis were seen in patients with elevated FABP4 expression [7].

Cell membrane require cholesterol for proper function and maintenance. Cells can either consume low-density lipoprotein (LDL) or produce cholesterol on their own. The Low-density lipoprotein receptor-related protein 1B (LRP1B) protein, which is associated with LDLRs, is a member of the LDLR family as well. Cytoplasmic LRP1B immune responses were significantly higher in gastric cancer patients [8].

Through the process of converting acetate to ACSSs, acetate becomes an essential chemical for histone acetylation and lipid synthesis. The only thing that significantly reduced acetate-mediated histone modification and lipid production was the down-regulation of Acyl-CoA Synthetase Short Chain Family Member 2 (ACSS2). Patients with gastric cancer (MSI) may have a worse prognosis in clinical settings if there is a lack of ACSS2 expression, which was found to be strongly linked to microsatellite instability. This lack of expression may serve as its independent prognostic factor.

De-novo fatty acid synthesis id dependent on ACYL. It converts substrate citrate into the acetyl CoA, which is necessary for cancer cells to grow and function properly. The ACLY’s transformation of citrate into acetyl-CoA kicks off fatty acid synthesis. HP causes gastritis and epithelial damage by releasing a protein which increases the acetyl CoA production and increases the expression of the ACLY gene and improves contact between HP and gastric epithelial cells.

Human stomach cancer typically causes Acetyl-CoA carboxylases (ACC) activation to rise to a higher level. A key prognostic factor, pACC deficiency, may have a significant impact on the progression of Gastric Cancer. When pACC expression was higher, the survival rates of all gastric cancer patients were higher. Low or missing pACC expression was significantly associated with poor GC cell differentiation status, advanced tumour stage, lymph node metastases, and lower survival rates compared to those with high pACC expression, particularly in the initial stages [9].

References

1. Sadowski, M. C., Pouwer, R. H., Gunter, J. H., Lubik, A. A., Quinn, R. J., & Nelson, C. C. (2014). The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer. Oncotarget, 5(19), 9362.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253440/

2. Horiguchi, Akio, et al. “Pharmacological inhibitor of fatty acid synthase suppresses growth and invasiveness of renal cancer cells.” The Journal of urology 180.2 (2008): 729-736.

Link: https://www.auajournals.org/doi/abs/10.1016/j.juro.2008.03.186

3. Lee, H. R., Hwang, K. A., Nam, K. H., Kim, H. C., & Choi, K. C. (2014). Progression of breast cancer cells was enhanced by endocrine-disrupting chemicals, triclosan and octylphenol, via an estrogen receptor-dependent signalling pathway in cellular and mouse xenograft models. Chemical research in toxicology, 27(5), 834-842.

Link: https://www.auajournals.org/doi/abs/10.1016/j.juro.2008.03.186

4. Schwenk, R. W., Holloway, G. P., Luiken, J. J., Bonen, A., & Glatz, J. F. (2010). Fatty acid transport across the cell membrane: regulation by fatty acid transporters. Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA), 82(4-6), 149-154.

Link: https://www.sciencedirect.com/science/article/pii/S0952327810000736?via%3Dihub

5. Gimeno, R. E. (2007). Fatty acid transport proteins. Current opinion in lipidology, 18(3), 271-276.

Link: https://journals.lww.com/co-lipidology/Abstract/2007/06000/Fatty_acid_transport_proteins.8.aspx

6. Lien, E. C., Lyssiotis, C. A., Juvekar, A., Hu, H., Asara, J. M., Cantley, L. C., & Toker, A. (2016). Glutathione biosynthesis is a metabolic vulnerability in PI (3) K/Akt-driven breast cancer. Nature cell biology, 18(5), 572-578.

Link: https://www.nature.com/articles/ncb3341

7. Nagini, S. (2012). Carcinoma of the stomach: A review of epidemiology, pathogenesis, molecular genetics, and chemoprevention. World journal of gastrointestinal oncology, 4(7), 156.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406280/

8. Zhao, J., Zhi, Z., Wang, C., Xing, H., Song, G., Yu, X., … & Di, Y. (2017). Exogenous lipids promote the growth of breast cancer cells via CD36. Oncology reports, 38(4), 2105-2115.

Link: https://www.spandidos-publications.com/or/3s8/4/2105

9. Tesfay, L., Paul, B. T., Konstorum, A., Deng, Z., Cox, A. O., Lee, J., … & Torti, S. V. (2019). Stearoyl-CoA desaturase 1 protects ovarian cancer cells from ferroptotic cell death. Cancer research, 79(20), 5355-5366.

Link: https://aacrjournals.org/cancerres/article/79/20/5355/638370/Stearoyl-CoA-Desaturase-1-Protects-Ovarian-Cancer