Autophagy: A challengeable paradox in cancer treatment

Abstract

Objective: Autophagy is an intracellular degradation pathway conserved in all eukaryotes from yeast to humans. This process plays a quality-control role by destroying harmful cellular components under normal conditions, maintaining cell survival, and establishing cellular adaptation under stressful conditions. Hence, there are various studies indicating dysfunctional autophagy as a factor involved in the development and progression of various human diseases, including cancer. In addition, the importance of autophagy in the development of cancer has been highlighted by paradoxical roles, as a cytoprotective and cytotoxic mechanism. Despite extensive research in the field of cancer, there are many questions and challenges about the roles and effects suggested for autophagy in cancer treatment. The aim of this study was to provide an overview of the paradoxical roles of autophagy in different tumors and related cancer treatment options.

Methods: In this study, to find articles, a search was made in PubMed and Google scholar databases with the keywords Autophagy, Autophagy in Cancer Management, and Drug Design.

Results: According to the investigation, some studies suggest that several advanced cancers are dependent on autophagy for cell survival, so when cancer cells are exposed to therapy, autophagy is induced and suppresses the anti-cancer effects of therapeutic agents and also results in cell resistance. However, enhanced autophagy from using anti-cancer drugs causes autophagy-mediated cell death in several cancers. Because autophagy also plays roles in both tumor suppression and promotion further research is needed to determine the precise mechanism of this process in cancer treatment.

Conclusion: We concluded in this article, autophagy manipulation may either promote or hinder the growth and development of cancer according to the origin of the cancer cells, the type of cancer, and the behavior of the cancer cells exposed to treatment. Thus, before starting treatment it is necessary to determine the basal levels of autophagy in various cancers.

Keywords: angiogenesis; autophagy; cancer biology; cancer management; drug design; signal transduction.

FIGURE 1

Autophagy process consists of several sequential steps. (1) Initiation. (2) Phagophore nucleation. (3) Phagophore elongation. (4) Fusion of autophagosome with lysosome and degradation of cargo in autolysosome.

FIGURE 2

Overview of signaling pathways involved in the regulation of autophagy. (1) Growth factors and nutrients can induce PI3K, which activates AKT and subsequently mTORC1. Also, the activated AKT induce mTORC1 through TSC1/2 inhibition. (2) Growth factors inducethe Ras–Raf–MEK‐ERK1/2 signaling pathway. This pathway can directly induce autophagy. ERK complex can inhibit TSC1/2 complex, leading to activating mTORC1. (3) Under starvation and stress condition, Bcl2 is phosphorylated by JNK1 and thereby separated from Beclin1. Then, Beclin1 induces Vps34 complex formation, an important protein complex in the autophagy process. (4) P53 has different roles in autophagy. Under stress conditions, p53 nuclear localization promotes autophagy inducers such as DRAM and DAPK1. Nevertheless, cytoplasmic p53 leads to autophagy inhibition through Beclin1 and AMPK blocking.