By Clarice Tse
The discovery of autophagy and its mechanism in action was elucidated by Yoshinori Ohsumi in the 1990s. As years passed, the expansion of knowledge in autophagy such as its role and function in bioenergetic homeostasis and host defense, and its impact in the study of human health and disease, has put this degradation pathway in the limelight. Autophagy is an evolutionarily conserved catabolic process of cellular degradation and recycling of cytoplasmic components. Its main role is to maintain cellular homeostasis when cells are under hypoxic, nutrient-deprived conditions (Pérez-Hernández et al., 2019). As it supports nutrient recycling and metabolic adaptation, it was implicated to regulate cancer.
Autophagy has five steps: initiation, elongation, maturation, fusion and degradation. Firstly, the cargos that include macromolecules and organelles are encompassed by a double-membrane vesicle. During elongation, the vesicle gradually extends and matures into an autophagosome. Next, autophagosome fuses with lysosome to form autolysosome, where the cargos are degraded by lysosomal hydrolase and lysosomal permease recycles the products back to the cytoplasm. ULK complex, which includes ULK1/2, Atg13, FIP200 and Atg101, is core machinery in initiation stage of autophagy. Beclin1-Vps34-Atg14L-p150 complex is the other key complex, needed in autophagosomal nucleation (Sun et al., 2013).
Cancer – the uncontrolled proliferation of genetically abnormal cells- is characterized by many properties or abilities which are termed “hallmarks of cancers” by the pioneer in cancer research, Robert Weinberg. One of the many hallmarks include cancer cell’s ability to evade tumour suppression. Cancer cells acquire genetic mutations or genetic variants that alters the function of genes that are normally involved in apoptosis, cell cycle arrest or DNA repair such as TP53 and RB. The genetic alterations cause dysregulation of the function of these genes which allows cancer cells to be unable to suppress growth and proliferation under conditions such as DNA damage. Hence, the formation and development of a primary tumour- tumourigenesis is promoted.
Autophagy was found to have dual roles in cancer. It can be tumour suppressive pre-oncogenesis and tumour promoting in advanced cancers. The multistep lysosomal degradation pathway is tightly regulated at the molecular level by a family of proteins called autophagy-related proteins (ATGs). At basal levels, autophagy functions as a mechanism for tumour suppression through the removal and reduction of oncogenic protein substrates, toxic unfolded proteins and organelles, this prevents chronic cellular damage which results in oncogenesis (White, 2012). Previous studies reported the depletion of the autophagy-related gene BECN1 (encoded for Beclin 1) in a variety of human breast, prostate and ovarian cancers. Beclin 1 is crucial to the formation of phagophore in autophagosome nucleation. Due to the loss of Beclin 1 cancer cells are unable to remove the self-aggregated oncogenic protein p62 which promotes tumorigenesis, leading to its accumulation (Yun and Lee, 2018 ; Li, He and Ma, 2020). In addition, reactive oxygen species and toxic products could also not be removed, hence contributing to the increased proliferation of cancer cells.
As cancer progresses, tumours are exposed to extremely stressful conditions including nutrient deprivation and hypoxia. The primary tumour utilizes mechanisms, like the altered cellular energetics such as the increased uptake of glucose and elevated glycolytic activity to generate energy readily for the proliferation of cells. It was found that after the formation of tumour, autophagy functions to overcome the stresses mentioned above. Its site of activity is mainly in the central part of solid tumours, where cancer cells are distant from blood vessels and therefore are the most nutrient and oxygen-deprived. This is because autophagy recycles organelles to nutrients such as amino acids which can be provided to support the metabolic processes of cancer cells when they are starved and under low oxygen levels. Accordingly, many types of advanced cancers show higher basal autophagic activity than normal tissues. (Pérez-Hernández et al., 2019).
The bipolar function of autophagy leads to the question of how autophagy can be targeted in cancer therapy. Currently, the selection of a successful therapeutic strategy targeting autophagy depends on the properties and characteristics of a patient’s tumour. For example, some cancers are p53-deficient. In the absence of p53, programmed cell death will also not be able to be triggered, leading to enhanced proliferation of cancer cells. In this case, “autophagic cell death” can be activated to kill the tumour cell by self-digestion and vacuolization of the cytoplasm beyond the point allowing self -survival. Therefore, compounds that activates autophagic cell death can be considered as potential anticancer drugs for p53-deficient cancers. (Pérez-Hernández et al., 2019)
On the other hand, some tumours use autophagy to mitigate cellular stress induced by cancer drugs. As aforementioned, autophagy can be a pro-survival mechanism present in most advanced tumours, it allows tumours to adapt to nutrient stress and hypoxia, thus enabling tumour progression. Therefore, inhibition of autophagy sensitizes cancer cells to therapy. One of the examples is pancreatic cancer, which requires autophagy for tumour progression, the high basal level of autophagy increases resistance to therapies (Yang et al., 2011). Hence, the inhibition of autophagy can be a potential therapeutic strategy to treat these tumours.
Autophagy possesses dual and contradicting roles in cancer development, whether autophagy is tumour suppressive or tumour promoting depends on the specific conditions and properties of the cancer and varies in different stages of development. Therefore, there are many ways of manipulating of autophagy to become suitable therapeutic strategies to different cancer types. It can be personalized to cater different cancer patients in order to make treatments more effective. By screening for specific variants and mutations, the genetic causes and factors that contributed to the cancer of the patient can be identified, next, different strategies targeting autophagy can be used, including autophagy inhibition and autophagy activation. The roles of autophagy in cancer is a broad topic involving many dimensions and physiological functions of the cells, such as immunologic function, cell death, tumour suppression and many more. Therefore, more research would be done in the future to elucidate the diverse roles of autophagy in cancer.
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