Altered Metabolism in Cancer via PI3K/Akt pathway

By Hung-Hsi Chen

Altered metabolism is one of the emerging hallmarks of cancer. The Warburg effect in cancer cells explains their ability to undergo glycolysis even under aerobic conditions to meet the energy demand. However, recent studies have been focusing on the reprogramming of fatty acid metabolism in cancer cells, and one of the most studied pathway is the phosphatidylinositol-3-kinase (PI3K)/ Akt/mammalian target of rapamycin (mTOR) signalling pathway. 

The PI3K/Akt/mTOR is one of the most studied pathway in cancer growth, proliferation survival and metabolism (Porta et al., 2014). Hence, this pathway is also one of the most targeted pathways in terms of therapeutic interventions. PI3K is recruited to the membrane by phosphorylation of tyrosine kinase. Activated PI3K leads to the activation of Protein Kinase B (Akt), which controls processes such as cell survival and cell cycle progression (Porta et al., 2014). Akt, has three conserved domains, the PH domain, CAT domain and an extension (EXT) containing regulatory hydrophobic motif (Yang et al., 2019). Using the hydrophobic motif, Akt gets activated upon the binding to PI3K (Yang et al., 2019).

Under standard physiological conditions, mTOR is positively regulated by insulin-like growth factors-1, human epidermal growth factor receptor family and vascular endothelial growth factor receptors (Porta et al., 2014). On the other hand, it is negatively regulated by a phosphatase and tensin homolog, tuberous sclerosis complex I and II (Porta et al., 2014). 

An important molecule, PTEN, which exists downstream of the PI3K/Akt pathway, is a tumour suppressor with a role in promoting apoptosis, and has an important part in negatively regulating the PI3K/Akt/mTOR signalling pathway. This pathway is often targeted in therapies due to its dysregulation in most cancers, like breast, colorectal and hematologic malignancies (Yang et al., 2019). Certain cancers, like prostate cancers rely more on lipid metabolism rather than aerobic glycolysis. An upregulation of cholesterol and de novo fatty acid synthesis has been observed in prostate cancer upon the loss of PTEN. Studies by Zhou et al. (2019) suggested that loss of PTEN can lead to reprogramming of lipid metabolism in cancer cells, including the beta-oxidation and de novo synthesis of fatty acids (Zhou et al., 2019). 

Fatty acids can be acquired through exogenous uptake from the cell’s microenvironment, or synthesised using glucose or glutamine (Koundouros et al., 2019). It has been made clear that cancer cells undergo lipidomic remodelling. As seen in breast, prostate and ovarian cancer, they prefer to be surrounded by adipocytes due to their ability to secrete growth factors, cytokines and fatty acids (Koundouros et al., 2019). These adipocytes help to secrete fatty acids through a cascade of events, that are eventually taken up by metastatic cells (Koundouros et al., 2019). An increased uptake of fatty acids in cancer cells are then stored as lipid droplets as a source of ATP and NADPH. Indeed, metastatic cells undergoing loss of attachment have been observed to inhibit glucose uptake despite their increased need for ATP (Koundouros et al., 2019). Instead, metastatic cancer cells utilise fatty acid oxidation to maintain their need for ATP during metastasis. 

As aforementioned, the PI3K/Akt pathway is often abnormal in cancer. Akt activation synthesises components required for lipogenesis and supply intermediates needed for anabolism, both of which are essential for synthesising lipids in cancer cells (Koundouros et al., 2019). 

Therefore, therapy can target multiple aspects of fatty acid metabolism. Firstly, targeting de novo fatty acid synthesis. Therapeutic agents that block sterol regulatory binding protein 1 (SREBP-1), a transcription factor regulating fatty acid synthesis (Chen et al., 2019). By inhibiting SREBP-1, tumour growth can be inhibited. Secondly, targeting fatty acid modification by inhibiting the uptake of exogenous fatty acids by cancer cells by blocking CD36, FATPs, LDLR and FABPs (Chen et al., 2019). Treatments blocking these membrane proteins have been used as potential anti-cancer therapies (Chen et al., 2019). Thirdly, targeting fatty acid storage and mobilisation. As aforementioned, excess intracellular fatty acids are stored as lipid droplets, which provides benefits such as preventing lipotoxicity and oxidative stress for tumour cells (Chen et al., 2019). Inhibition of lipid droplet formation by blocking molecules involved in the process like lysophosphatidylcholine acytransferase 2 and FABPs can increase lipotoxicity in cancer cells, hence promoting cell death and inhibiting cell growth (Chen et al., 2019). 

Understanding the ability of cancer cells to adopt different metabolic pathways to survive acts as a potential to novel therapies. Although therapies targeting fatty acid metabolism already exist, more research needs to be done for it to be targeted on a specific type of cancer on a specific component of the complex PI3K/Akt/mTOR signalling pathway. 

References:

Chen, M. & Huang, J. 2019, “The expanded role of fatty acid metabolism in cancer: new aspects and targets”, Precision clinical medicine, vol. 2, no. 3, pp. 183-191.

Koundouros, N. & Poulogiannis, G. 2019, “Reprogramming of fatty acid metabolism in cancer”, British journal of cancer, vol. 122, no. 1, pp. 4-22.

Porta, C., Paglino, C. & Mosca, A. 2014, “Targeting PI3K/Akt/mTOR Signaling in Cancer”, Frontiers in oncology, vol. 4, pp. 64.

Yang, J., Nie, J., Ma, X., Wei, Y., Peng, Y. & Wei, X. 2019, “Targeting PI3K in cancer: mechanisms and advances in clinical trials”, Molecular cancer, vol. 18, no. 1, pp. 26.

Zhou, X., Yang, X., Sun, X., Xu, X., Li, X., Guo, Y., Wang, J., Li, X., Yao, L., Wang, H. & Shen, L. 2019, “Effect of PTEN loss on metabolic reprogramming in prostate cancer cells”, Oncology letters, vol. 17, no. 3, pp. 2856-2866.