Authors:
Sujit K. Bhutia, Timothy P. Kegelman, Swadesh K. Das, Belal Azab, Zhao-zhong Su, Seok-Geun Lee, Devanand Sarkara, and Paul B. Fisher
Summary:
Astrocyte-elevated gene-1 (AEG-1) expression increases in multiple cancers and plays a crucial role in oncogenic transformation and angiogenesis, which are essential components in tumor cell development, growth, and progression to metastasis. Moreover, AEG-1 directly contributes to resistance to chemotherapeutic drugs, another important hallmark of aggressive cancers. In the present study, we document that AEG-1 mediates protective autophagy, an important regulator of cancer survival under metabolic stress and resistance to apoptosis, which may underlie its significant cancer-promoting properties. AEG-1 induces noncanonical autophagy involving an increase in expression of ATG5. AEG-1 decreases the ATP/AMP ratio, resulting in diminished cellular metabolism and activation of AMP kinase, which induces AMPK/mammalian target of rapamycin-dependent autophagy. Inhibition of AMPK by siAMPK or compound C decreases expression of ATG5, ultimately attenuating AEG-1–induced autophagy. AEG-1 protects normal cells from serum starvation-induced death through protective autophagy, and inhibition of AEG-1–induced autophagy results in serum starvation-induced cell death. We also show that AEG-1–mediated chemoresistance is because of protective autophagy and inhibition of AEG-1 results in a decrease in protective autophagy and chemosensitization of cancer cells. In summary, the present study reveals a previously unknown aspect of AEG-1 function by identifying it as a potential regulator of protective autophagy, an important feature of AEG-1 that may contribute to its tumor-promoting properties.
Source:
Proceedings of the National Academy of Sciences of the United States of America; Vol. 107, No. 51, 22243-22248 (12/21/10)