Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis

Guo, J. Y., Chen, H.-Y., Mathew, R., et al. Genes & Development (2011) 25; 1-11

Speaker：Yu-Chan Yang (楊于嬋)                                       Time：14:00~15:00, Mar. 30 2011

Commentator：Dr. Pei- Jung Frank Lu (呂佩融 教授)      Place：Room 601

Abstract：

Ras oncogene promotes the initiation of tumorigenesis and maintains tumor growth. Human cancers frequently express activated mutant Ras proteins. Previous studies mentioned that Ras also can induce autophagy¹. Autophagy is an evolutionarily conserved catabolic process, which supports metabolism in response to starvation and regulates organelles degradation. In tumor cells, apoptosis deficiency allows autophagy to prolong cell survival, indicating that cancer cells use the catabolic function of autophagy to tolerate stress². However, autophagy promotes survival in ras-related tumors in starvation is not clear. The authors reported that H-ras^V12 or K-ras^V12 oncogene up-regulated basal autophagy, which is required for tumor cell survival in starvation and in tumorigenesis. In Ras-expressing cells, p62 deficiency or impaired autophagosome formation causes accumulation of mitochondria and depletion of TCA cycle metabolites. Autophagy deficiency also reduces oxygen consumption and results in energy depletion. In human cancer cell lines, Ras activation induces autophagy to maintain normal cell growth and survival. The cancers such as lung, pancreas and colon with high activated-mutant Ras normally have poor prognosis. Therefore, development of specific autophagy inhibitor and targeting mitochondrial metabolism are potential strategies to treat this “autophagy addiction” cancer.

References：

1. Mathias T. Rosenfeldt and Kevin M. Ryan 2009 The role of autophagy in tumour development and cancer therapy Expert Rev Mol Med. 11; 1-20

2. Mathew R, et al. 2007a. Role of autophagy in cancer. Nat Rev Cancer 7: 961–967.