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Author Notes:

Corresponding Author: Xingming Deng, Division of Cancer Biology, Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA. Phone: (404)778-3398; xdeng4@emory.edu

Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed.


Research Funding:

This work was supported by a Scholarship Award from the China Scholarship Council (CSC) (YL), by Flight Attendant Medical Research Institute Clinical Innovator Awards (XD), by NCI, National Institutes of Health Grants R01CA112183 (XD), R01CA136534 (XD), R01CA118450 (SYS) and NIH lung cancer P01 CA116676 (FRK and SYS), and by a Kennedy Seed Grant from the Winship Cancer Institute (XD).

Rapamycin Induces Bad Phosphorylation in Association with Its Resistance to Human Lung Cancer Cells


Journal Title:

Molecular Cancer Therapeutics


Volume 11, Number 1


, Pages 45-56

Type of Work:

Article | Post-print: After Peer Review


Inhibition of mTOR signaling by rapamycin has been demonstrated to activate ERK1/2 and Akt in various types of cancer cells, which contributes to rapamycin resistance. However, the downstream effect of rapamycin-activated ERKs and Akt on survival or death substrate(s) remains unclear. We discovered that treatment of human lung cancer cells with rapamycin results in enhanced phosphorylation of Bad at serine (S) 112 and S136 but not S155 in association with activation of ERK1/2 and Akt. A higher level of Bad phosphorylation was observed in rapamycin-resistant cells compared to parental rapamycin-sensitive cells. Thus, Bad phosphorylation may contribute to rapamycin resistance. Mechanistically, rapamycin promotes Bad accumulation in the cytosol, enhances Bad/14-3-3 interaction and reduces Bad/Bcl-XL binding. Rapamycin-induced Bad phosphorylation promotes its ubiquitination and degradation, with a significant reduction of its half-life (i.e. from 53.3 h to 37.5 h). Inhibition of MEK/ERK by PD98059 or depletion of Akt by RNA interference blocks rapamycin-induced Bad phosphorylation at S112 or S136, respectively. Simultaneous blockage of S112 and S136 phosphorylation of Bad by PD98059 and silencing of Akt significantly enhances rapamycin-induced growth inhibition in vitro and synergistically increases the anti-tumor efficacy of rapamycin in lung cancer xenografts. Intriguingly, either suppression of Bad phosphorylation at S112 and S136 sites or expression of the non-phosphorylatable Bad mutant (S112A/S136A) can reverse rapamycin resistance. These findings uncover a novel mechanism of rapamycin resistance, which may promote the development of new strategies for overcoming rapamycin resistance by manipulating Bad phosphorylation at S112 and S136 in human lung cancer.

Copyright information:

©2011 American Association for Cancer Research.

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