Oncogenes and tumor suppressor genes in autophagy

Abstract

The autophagy pathway has a clear, dual role in cancer development: autophagy inhibition increases tumor initiation, but for established tumors, autophagy inhibitors can potently suppress tumor progression. Given the role of autophagy in tumor initiation, it is perhaps not surprising that many oncogenes that are commonly found mutated in human cancer negatively regulate this process. Conversely a major tumor suppressor pathway, the p53/ARF axis, positively regulates autophagy. Notably, the majority of human tumors contain activated oncogenes that are predicted to lead to hyper-activation the PI3K/AKT/mTOR pathway. Additionally, most tumors contain inactivating mutations in the p53/ARF pathway. Therefore, it is reasonable to predict that cancer cells have an impaired ability to undergo autophagy, but at the same time a hyper-reliance on this pathway to promote survival during metabolic and hypoxic stress. As such, the autophagy pathway is likely to be an Achilles heel for cancer. Exploiting this weakness will be an important future goal for cancer researchers.