Autophagy and tumorigenesis

Abstract

Autophagy is a catabolic process that captures cellular waste and degrades them in the lysosome. The main functions of autophagy are quality control of cytosolic proteins and organelles, and intracellular recycling of nutrients in order to maintain cellular homeostasis. Autophagy is upregulated in many cancers to promote cell survival, proliferation, and metastasis. Both cell-autonomous autophagy (also known as tumor autophagy) and non-cell-autonomous autophagy (also known as host autophagy) support tumorigenesis through different mechanisms, including inhibition of p53 activation, sustaining redox homeostasis, maintenance of essential amino acids levels in order to support energy production and biosynthesis, and inhibition of antitumor immune responses. Therefore, autophagy may serve as a tumor-specific vulnerability and targeting autophagy could be a novel strategy in cancer treatment.

Keywords: autophagy; cancer; cancer metabolism; cancer treatment; immune response; metastasis; p53.

Figure 1.. Autophagy regulatory pathways

The PI3K/AKT/mTOR pathway, activated by nutrients and growth factors, leads to downregulation of autophagy. On the other hand, the LKB1/AMPK/ULK pathway leads to upregulation of autophagy due to metabolic stressors.

Figure 2.. Autophagy machinery

Step 1, the phagophore is synthesized from ER membrane lipids upon activation by the Vps34 Complex. Step 2, the phagophore is elongated with the help of structural proteins such as LC3 and GABARAP. These Atg8 family of proteins are attached to the phagophore with the help of ATG complexes. Step 3, p62 and NBR1 serve as cargo receptor proteins that carry polyubiquitinated proteins destined for degradation to the phagophore. Once the phagophore closes itself around the protein, it is known as an autophagosome. Step 4, a neighboring lysosome then fuses with the autophagosome to create and autolysosome. Step 5, the polyubiquitinated protein is degraded using lysosomal enzymes.

Figure 3.. Common functions of autophagy

Autophagy degrades damaged or dysfunctional cytosolic organelles and proteins, serving as a quality control and waste disposal mechanism for the cell. Autophagy-mediated degradation also serves as a way for the cell to recycle nutrients and other substrates for use in biosynthesis and energy production - especially during times of stress or starvation.

Figure 4.. Autophagy modulates immune response for tumor progression

A. Non-cell autonomous autophagy supports immune evasion for tumor growth. Hepatic autophagy suppresses STING and IFNγ activation to prevent tumor killing by T cells [67]. B. Cell autonomous autophagy promotes tumor growth via: 1) reduction of antigen presentation [71, 72] and 2) inhibition of cytotoxic T cell infiltration into the tumor [76, 77]. In certain types of lung cancers, 3) ablation of autophagy has been shown to activate regulatory T cells, thus promoting tumorigenesis [82, 83].

Figure 5.. Autophagy Supports Cancer Cell Metabolism

A. Ablation of cell autonomous autophagy in tumor cells leads to a variety of outcomes: 1) lowered levels of amino acids, ATP production, and nucleotides synthesis due to reduced substrate recycling [29, 89, 90], 2) defective FAO and increased sensitivity to FAO inhibition [28, 30], 3) p53 induction [, –97], and 4) higher basal ROS levels [29]. B. Ablation of non-cell autonomous autophagy causes various outcomes in the host and the TME: 1) Ablation of host autophagy or liver autophagy causes the release of Arginase I from hepatocytes, thereby reducing circulating arginine that is essential for tumor growth [31], 2) Ablation of systemic autophagy also leads to deduced metabolites in the TME, leading to tumor death [31], 3) Ablation of systemic autophagy is associated with reduced mTOR activity, impairing tumor growth [27, 31], and 4) ablation of autophagy in stromal cells of PDAC restrains the supply of metabolites to tumor cells [33]. Figure Template Taken from BioRender.com [169].

Figure 6.. Autophagy in cancer treatment

Autophagy inhibition in combination with other cancer treatments can potentiate overall treatment effectiveness and overcome resistance. One common cancer treatment involves the use of RAS/RAF/MEK/ERK pathway inhibitors, but tumor cells can adapt resistance to this therapeutic strategy. ERK inhibition can partially downregulate mTOR activity, leading to de-repression and activation of protective autophagy, which may partially explain tumor adaptation to ERK pathway inhibitors such MEK inhibitors. Combining an ERK inhibitor with both autophagy inhibition and mTOR inhibition can therefore overcome resistance pathways and increase overall response to these treatments.