Autophagy in Cancer: Regulation by Small Molecules

Abstract

During times of stress, autophagy is a cellular process that enables cells to reclaim damaged components by a controlled recycling pathway. This mechanism for cellular catabolism is dysregulated in cancer, with evidence indicating that cancer cells rely on autophagy in the hypoxic and nutrient-poor microenvironment of solid tumors. Mounting evidence suggests that autophagy has a role in the resistance of tumors to standard-of-care (SOC) therapies. Therefore, there is significant interest in the discovery of small molecules that can safely modulate autophagy. In this review, we describe recent advances in the identification of new pharmacological compounds that modulate autophagy, with a focus on their mode of action, value as probe compounds, and validation as potential therapeutics.

Keywords: autophagosome; autophagy; cancer; kinase; oncology.

Figure 1:. Overview of the Modulation of Autophagy.

The formative stages of autophagy, protein components, and points of modulation by small molecules are indicated. Under conditions of nutrient deprivation mTOR is inactivated and AMPK is activated. These metabolic sensor proteins phosphorylate negative and positive regulatory sites on ULK1/2 kinase in the context of the “preinitiation complex”. The preinitiation complex activates the “initiation complex” or the “class III PI-IIIK complex” via phosphorylation of VPS34 and Beclin-1. Regulation of the initiation complex has a direct effect on the production of cellular pools of phosphatidylinositol3-phosphate (PI3P) from the precursor phosphatidylinositol (PI) needed for nucleation of the isolation membrane. Cellular concentrations of the initiation complex are also under the control of an ubiquitination cascade regulated by the deubiquitination peptidases USP10 and USP13. Expansion of nascent precursor vesicles relies on the autophagosome protein LC3. Critical for this process is the phosphatidylethanolamine (PE) conjugated form of the LC3 protein called LC3-II. The generation of LC3-II is derived from the “LC3 elongation sequence” of modifying enzymes. LC3-I is the product of proteolytic cleavage of proLC3 by the protease ATG-4B. LC3-I is then lipidated by a series of conjugating enzymes to the LC3-II form which stably associates with mature autophagosomal membranes. The versatile scaffold protein p62 plays a role in the trafficking of proteins to the autophagosome and is an important component of apoptosis pathways. In autophagy, p62 stably binds to the LC3-II protein in the context of assembling autophagosomes.