Autophagic pathways as new targets for cancer drug development

Abstract

Autophagy is an evolutionarily conserved lysosomal self-digestion process involved in degradation of long-lived proteins and damaged organelles. In recent years, increasing evidence indicates that autophagy is associated with a number of pathological processes, including cancer. In this review, we focus on the recent studies of the evolutionarily conserved autophagy-related genes (ATGs) that are implicated in autophagosome formation and the pathways involved. We discuss several key autophagic mediators (eg, Beclin-1, UVRAG, Bcl-2, Class III and I PI3K, mTOR, and p53) that play pivotal roles in autophagic signaling networks in cancer. We discuss the Janus roles of autophagy in cancer and highlighted their relationship to tumor suppression and tumor progression. We also present some examples of targeting ATGs and several protein kinases as anticancer strategy, and discuss some autophagy-modulating agents as antitumor agents. A better understanding of the relationship between autophagy and cancer would ultimately allow us to harness autophagic pathways as new targets for drug discovery in cancer therapeutics.

Figure 1

Multiple stages of autophagy flow and the molecular regulators.

Figure 2

Binding of Beclin 1 with its regulators. (A) Binding of Beclin 1 BH3 domain with the BC groove of Bcl-2. (B) The schematic representations of the Bcl-2-Beclin1-Class III PI3K-UVRAG-Bif-1 multi-protein complex.

Figure 3

The schematic model of autophagic signaling pathways in cancer.