Research Papers: Autophagy and Cell Death:

Overexpression of Bcl-2 induces STAT-3 activation via an increase in mitochondrial superoxide

Jia Kang, Stephen Jun Fei Chong, Vignette Zi Qi Ooi, Shireen Vali, Ansu Kumar, Shweta Kapoor, Taher Abbasi, Jayshree L. Hirpara, Thomas Loh, Boon Cher Goh and Shazib Pervaiz _

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Oncotarget. 2015; 6:34191-34205. https://doi.org/10.18632/oncotarget.5763

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Jia Kang1, Stephen Jun Fei Chong1, Vignette Zi Qi Ooi1, Shireen Vali2, Ansu Kumar3, Shweta Kapoor3, Taher Abbasi2, Jayshree L. Hirpara4, Thomas Loh5, Boon Cher Goh4 and Shazib Pervaiz1,6,7,8

1 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

2 Cellworks Group Inc., San Jose, CA, USA

3 Cellworks Research India Private Limited, Bangalore, India

4 Experimental Therapeutics Program, Cancer Science Institute, Singapore, Singapore

5 Department of Otolaryngology, National University Healthcare System, Singapore, Singapore

6 NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore

7 National University Cancer Institute, NUHS, Singapore, Singapore

8 School of Biomedical Sciences, Curtin University, Perth, Australia

Correspondence to:

Shazib Pervaiz, email:

Keywords: Bcl-2, Rac1, STAT3, superoxide, mitochondria

Received: July 08, 2015 Accepted: September 07, 2015 Published: September 27, 2015


We recently reported a novel interaction between Bcl-2 and Rac1 and linked that to the ability of Bcl-2 to induce a pro-oxidant state in cancer cells. To gain further insight into the functional relevance of this interaction, we utilized computer simulation based on the protein pathway dynamic network created by Cellworks Group Inc. STAT3 was identified among targets that positively correlated with Rac1 and/or Bcl-2 expression levels. Validating this, the activation level of STAT3, as marked by p-Tyr705, particularly in the mitochondria, was significantly higher in Bcl-2-overexpressing cancer cells. Bcl-2-induced STAT3 activation was a function of GTP-loaded Rac1 and NADPH oxidase (Nox)-dependent increase in intracellular superoxide (O2•-). Furthermore, ABT199, a BH-3 specific inhibitor of Bcl-2, as well as silencing of Bcl-2 blocked STAT3 phosphorylation. Interestingly, while inhibiting intracellular O2•- blocked STAT3 phosphorylation, transient overexpression of wild type STAT3 resulted in a significant increase in mitochondrial O2•- production, which was rescued by the functional mutants of STAT3 (Y705F). Notably, a strong correlation between the expression and/or phosphorylation of STAT3 and Bcl-2 was observed in primary tissues derived from patients with different sub-sets of B cell lymphoma. These data demonstrate the presence of a functional crosstalk between Bcl-2, Rac1 and activated STAT3 in promoting a permissive redox milieu for cell survival. Results also highlight the potential utility of a signature involving Bcl-2 overexpression, Rac1 activation and STAT3 phosphorylation for stratifying clinical lymphomas based on disease severity and chemoresistance.

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