Critical Role of Sestrin2 in Regulating Nrf2/Keap1 Pathway and Mediating Autophagy in Colon Cancer
Showket Yahya* and G Sudhandiran
Cell Biology Laboratory, Department of Biochemistry, University of Madras, Guindy Campus, Chennai
*Corresponding Author: Showket Yahya, Cell Biology Laboratory, Department of Biochemistry, University of Madras, Guindy Campus, Chennai, India.
December 31, 2021; Published: January 01, 2022
Colon cancer also called colorectal cancer has become one of the deadliest cancers with incidence rates of 4.3% and 4.10% in men and women respectively. It has been reported that CRC is mainly due to cellular/ER stresses such as hypoxia, which may lead to the accumulation of reactive oxygen species (ROS). So, it is essential to scavenge these ROS. Sestrin2 (Sesn2) is known to suppress ROS accumulation by regulating various signalling pathways such as Nrf2/Keap1 pathways and maintaining mitochondrial homeostasis through the AMPK/mTOR pathway etc., thereby inducing autophagy. This review provides an overview of the Nrf2-Keap1 signalling pathway, the dual role of Nrf2, and autophagy in cancer, along with the role of sestrin2 in triggering autophagy in colon cancer cells.
Keywords: Colon Cancer; Cellular/Er Stress; ROS; Homeostasis; Sestrin2; Nrf2/Keap1 Signalling Pathway; Autophagy
- Geismann C., et al. “Cytoprotection “gone astray”: Nrf2 and its role in cancer”. OncoTargets and Therapy 7 (2014): 1497-1518.
- Pan C., et al. “Sestrin2 as a gatekeeper of cellular homeostasis: Physiological effects for the regulation of hypoxia-related diseases”. Journal of Cellular and Molecular Medicine 12 (2021): 5341-5350.
- Yun CW and Lee SH. “The Roles of Autophagy in Cancer”. International Journal of Molecular Sciences 11 (2018): 3466.
- Yang Y., et al. “Levistolide A induces apoptosis via ROS mediated ER stress pathway in colon cancer cells”. Cellular Physiology and Biochemistry 42 (2017): 929-938.
- Banerjee A., et al. “Increased reactive oxygen species levels cause ER stress and cytotoxicity in andrographolide treated colon cancer cells”. Oncotarget 16 (2017): 26142-26153.
- Hild JC., et al. “DHA induced ER stress and growth arrest in human colon cancer cells: associations with cholesterol and calcium homeostasis”. Journal of Lipid Research 49 (2008): 2089-2100.
- Park JW., et al. “Resveratrol induces pro-apoptotic endoplasmic reticulum stress in human colon cancer cells”. Oncology Reports 5 (2007): 1269-1273.
- Zhang J., et al. “Curcumin derivative WZ35 efficiently suppresses colon cancer progression through inducing ROS production and ER stress-dependent apoptosis”. American Journal of Cancer Research 2 (2017): 275-288.
- Basile V., et al. “bis-Dehydroxy-Curcumin triggers mitochondrial-associated cell death in human colon cancer cells through ER-stress induced autophagy”. PLOS ONE (2013).
- Kim TG., et al. “Quercetin regulated sestrin 2-AMPK-mTOR signalling pathway and induces apoptosis via increased intracellular ROS in HCT116 colon cancer cells”. European Journal of Cancer Prevention 3 (2013): 264-270.
- Jaramillo CM and Zhang DD. “The emerging role of the Nrf2-Keap1 signalling pathway in cancer”. Genes Development 20 (2013): 2179-2191.
- Donquiles CG., et al. “The NRF2 transcription factor plays a dual role in colorectal cancer: A systematic review”. PLoS One5 (2017): e0177549.
- Lee YJ., et al. “Overexpression of Nrf2 promotes colon cancer progression via ERK and AKT signaling pathways”. Annals of Surgical Treatment and Research 4 (2020): 159-167.
- Cernigliaro C., et al. “Ethanol-Mediated Stress Promotes Autophagic Survival and Aggressiveness of Colon Cancer Cells via Activation of Nrf2/HO-1 Pathway”. Cancers (Basel) 4 (2019): 505.
- Kim TH., et al. “NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-α”. Cancer Research 6 (2011): 2260-2275.
- Li CQ., et al. “Nitric oxide activation of Keap1/Nrf2 signalling in human colon carcinoma cells”. PNAS 34 (2009): 14547-14551.
- Song MY., et al. “The role of NRF2/KEAP1 signalling pathway in cancer metabolism”. International Journal of Molecular Sciences 9 (2021): 4376.
- Lee DY., et al. “Role of oxidative stress and Nrf2/KEAP1 signalling in colorectal cancer: Mechaisms and Therapeutic perspectives with phytochemicals”. Antioxidants (Basel)5 (2021): 743.
- Seo K., et al. “5-Fluorouracil inhibits cell migration by induction of Sestrin2 in colon cancer cells”. Archives of Pharmacal Research2 (2017): 231-239.
- Jeong S., et al. “Docosahexaenoic acid enhances oxaliplatin-induced autophagic cell death via the ER stress/Sesn2 pathway in colorectal cancer”. Cancers (Basel) 7 (2019): 982.
- Sun W., et al. “The emerging role of Sestrin2 in cell metabolism, and cardiovascular and age-related diseases”. Aging and Disease 1 (2020): 154-163.
- Ro SH., et al. “Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis”. Elife 5 (2016): e12204.
- Wei LJ., et al. “Sestrin 2 suppresses cells proliferation through AMPK/mTORC1 pathway activation in colorectal cancer”. Oncotarget 30 (2017): 49318-49328.
- Qu J., et al. “A paradoxical role of sestrin 2 protein in tumor suppression and tumorigenesis”. Cancer Cell International 1 (2021): 606.
- Kim H., et al. “The interaction of Hemin and Sestrin2 modulates oxidative stress and colon tumor growth”. Toxicology and Applied Pharmacology 374 (2019): 77-85.
- Wei JL., et al. “Decreased expression of sestrin 2 predicts unfavorable outcome in colorectal cancer”. Oncology Reports 3 (2015): 1349-1357.
- Panigrahi DP., et al. “The emerging, multifaceted role of mitophagy in cancer and cancer therapeutics”. Seminars in Cancer Biology 66 (2020): 45-58.
- Vara-Perez M., et al. “Mitophagy in cancer: A tale of adaptation”. Cells 5 (2021): 493.
- Jegal KH., et al. “Eupatilin induces Sestrin2-dependent autophagy to prevent oxidative stress”. Apoptosis 21 (2016): 642-656.
- Maiuri MC., et al. “Stimulation of autophagy by the p53 target gene Sestrin2”. Cell Cycle10 (2009): 1571-1576.
- Yang ZJ., et al. “The role of autophagy in cancer: therapeutic implications”. Molecular Cancer Therapeutics 9 (2011): 1533-1541.
- Li S., et al. “Combination of rapamycin and garlic-derived S-allylmercaptocysteine induces colon cancer cell apoptosis and suppresses tumor growth in xenograft nude mice through autophagy/p62/Nrf2 pathway”. Oncology Reports (2017): 1637-1644.
- Celesia A., et al. “ROS-dependent ER stress and autophagy mediate the anti-tumor effects of Tributylin (IV) Ferulate in colon cancer cells”. International Journal of Molecular Sciences 21 (2020): 8135.
- Liu HY., et al. “GLS1 depletion inhibited colorectal cancer proliferation and migration via redox/Nrf2/autophagy-dependent pathway”. Archives of Biochemistry and Biophysics 708 (2021): 108964.
- Liu X., et al. “Inhibition of phosphatidylinositide 3-kinase impairs the benzyl isothiocyanate-induced accumulation of autophagic molecules and Nrf2 in human colon cancer cells”. Bioscience, Biotechnology, and Biochemistry 11 (2017): 2212-2215.
- Trivedi PP., et al. “Melatonin modulated autophagy and Nrf2 signaling pathways in mice with colitis-associated colon carcinogenesis”. Molecular Carcinogenesis3 (2016): 255-267.
- Enkhbat T., et al. “Epigallocatechin-3-gallate enhances radiation sensitivity in colorectal cancer cells through Nrf2 activation and autophagy”. Anticancer Research 11 (2018): 6247-6252.
- Sena P., et al. “Metformin induces apoptosis and alters cellular responses to oxidative stress in Ht29 colon cancer cells: Preliminary Findings”. International Journal of Molecular Sciences 5 (2018): 1478.
- Pettersen K., et al. “DHA-induced stress response in human colon cancer cells - Focus on oxidative stress and autophagy”. Free Radical Biology and Medicine 90 (2016): 158-172.
- Sakitani K., et al. “Inhibition of autophagy exerts anti-colon cancer cefffects via apoptosis induced by p53 activation and ER stress”. BMC Cancer 15 (2015): 795.
- Li DD., et al. “The Inhibition of Autophagy Sensitises Colon Cancer Cells with Wild-Type p53 but Not Mutant p53 to Topotecan Treatment”. PLOS ONE (2012).