title: MTOR inhibition attenuates DNA damage and apoptosis through autophagy-mediated suppression of CREB1.
abstract: Hyperactivation of mechanistic target of rapamycin (MTOR) is a common feature of human cancers, and MTOR inhibitors, such as rapamycin, are thus becoming therapeutics in targeting certain cancers. However, rapamycin has also been found to compromise the efficacy of chemotherapeutics to cells with hyperactive MTOR. Here, we show that loss of TSC2 or PTEN enhanced etoposide-induced DNA damage and apoptosis, which was blunted by suppression of MTOR with either rapamycin or RNA interference. cAMP response element-binding protein 1 (CREB1), a nuclear transcription factor that regulates genes involved in survival and death, was positively regulated by MTOR in mouse embryonic fibroblasts (MEFs) and cancer cell lines. Silencing Creb1 expression with siRNA protected MTOR-hyperactive cells from DNA damage-induced apoptosis. Furthermore, loss of TSC2 or PTEN impaired either etoposide or nutrient starvation-induced autophagy, which in turn, leads to CREB1 hyperactivation. We further elucidated an inverse correlation between autophagy activity and CREB1 activity in the kidney tumor tissue obtained from a TSC patient and the mouse livers with hepatocyte-specific knockout of PTEN. CREB1 induced DNA damage and subsequent apoptosis in response to etoposide in autophagy-defective cells. Reactivation of CREB1 or inhibition of autophagy not only improved the efficacy of rapamycin but also alleviated MTOR inhibition-mediated chemoresistance. Therefore, autophagy suppression of CREB1 may underlie the MTOR inhibition-mediated chemoresistance. We suggest that inhibition of MTOR in combination with CREB1 activation may be used in the treatment of cancer caused by an abnormal PI3K-PTEN-AKT-TSC1/2-MTOR signaling pathway. CREB1 activators should potentiate the efficacy of chemotherapeutics in treatment of these cancers.
authors.affiliation: State Key Laboratory of Medical Molecular Biology; Department of Physiology; Institute of Basic Medical Sciences and School of Basic Medicine; Graduate School of Peking Union Medical College; Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhongdong
authors.initials: Z
authors.lastname: Hu
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Liu
authors.forename: Rongrong
authors.initials: R
authors.lastname: Chen
authors.forename: Haiyong
authors.initials: H
authors.lastname: Peng
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.forename: Xinxin
authors.initials: X
authors.lastname: Chen
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000502:physiology*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D005047:Etoposide; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: DNA damage; apoptosis; autophagy; cAMP response element-binding protein 1; chemoresistance; mechanistic target of rapamycin