Work

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

Year: 2017

Type: article

Abstract: // Benjamin Onyeagucha 1, 2 , Panneerdoss Subbarayalu 1, 2 , Nourhan Abdelfattah 1, 2 , Subapriya Rajamanickam 1, 2 , Santosh Timilsina 1, 2 , Rosa Guzman 1 , Carla Zeballos 2 , Vijay Eedunuri 1, 2 , Sanjay Bansal 1 , Tabrez Mohammad 2 , Yidong Chen 1, 3 , Ratna K. Vadlamudi 4 and Manjeet K. Rao 1, 2 1 Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, Texas, 78229 USA 2 Department of Cell Systems and Anatomy, The University of Texas Health Science Center at San Antonio, Texas, 78229 USA 3 Department of Epidemiology and Statistics, The University of Texas Health Science Center at San Antonio, Texas, 78229 USA 4 Department 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.20841