Oncotarget

Research Papers:

Novel post-transcriptional and post-translational regulation of pro-apoptotic protein BOK and anti-apoptotic protein Mcl-1 determine the fate of breast cancer cells to survive or die

Benjamin Onyeagucha, Panneerdoss Subbarayalu, Nourhan Abdelfattah, Subapriya Rajamanickam, Santosh Timilsina, Rosa Guzman, Carla Zeballos, Vijay Eedunuri, Sanjay Bansal, Tabrez Mohammad, Yidong Chen, Ratna K. Vadlamudi _ and Manjeet K. Rao

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Oncotarget. 2017; 8:85984-85996. https://doi.org/10.18632/oncotarget.20841

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Abstract

Benjamin Onyeagucha1,2, Panneerdoss Subbarayalu1,2, Nourhan Abdelfattah1,2, Subapriya Rajamanickam1,2, Santosh Timilsina1,2, Rosa Guzman1, Carla Zeballos2, Vijay Eedunuri1,2, Sanjay Bansal1, Tabrez Mohammad2, Yidong Chen1,3, Ratna K. Vadlamudi4 and Manjeet K. Rao1,2

1Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, Texas, 78229 USA

2Department of Cell Systems and Anatomy, The University of Texas Health Science Center at San Antonio, Texas, 78229 USA

3Department of Epidemiology and Statistics, The University of Texas Health Science Center at San Antonio, Texas, 78229 USA

4Department of Obstetrics and Gynecology, The University of Texas Health Science Center at San Antonio, Texas, 78229 USA

Correspondence to:

Manjeet K. Rao, email: [email protected]

Keywords: breast cancer, apoptosis, BOK, Mcl-1, GSK3α/β

Received: April 19, 2017    Accepted: August 04, 2017    Published: September 12, 2017

ABSTRACT

Deregulation of apoptosis is central to cancer progression and a major obstacle to effective treatment. The Bcl-2 gene family members play important roles in the regulation of apoptosis and are frequently altered in cancers. One such member is pro-apoptotic protein Bcl-2-related Ovarian Killer (BOK). Despite its critical role in apoptosis, the regulation of BOK expression is poorly understood in cancers. Here, we discovered that miR-296-5p regulates BOK expression by binding to its 3’-UTR in breast cancers. Interestingly, miR-296-5p also regulates the expression of anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1), which is highly expressed in breast cancers. Our results reveal that Mcl-1 and BOK constitute a regulatory feedback loop as ectopic BOK expression induces Mcl-1, whereas silencing of Mcl-1 results in reduced BOK levels in breast cancer cells. In addition, we show that silencing of Mcl-1 but not BOK reduced the long-term growth of breast cancer cells. Silencing of both Mcl-1 and BOK rescued the effect of Mcl-1 silencing on breast cancer cell growth, suggesting that BOK is important for attenuating cell growth in the absence of Mcl-1. Depletion of BOK suppressed caspase-3 activation in the presence of paclitaxel and in turn protected cells from paclitaxel-induced apoptosis. Furthermore, we demonstrate that glycogen synthase kinase (GSK3) α/β interacts with BOK and regulates its level post-translationally in breast cancer cells. Taken together, our results suggest that fine tuning of the levels of pro-apoptotic protein BOK and anti-apoptotic protein Mcl-1 may decide the fate of cancer cells to either undergo apoptosis or proliferation.


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