ROCK inhibitor reduces Myc-induced apoptosis and mediates immortalization of human keratinocytes
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Aleksandra Dakic1,2, Kyle DiVito3, Shuang Fang1,2, Frank Suprynowicz1,2, Anirudh Gaur3, Xin Li4, Nancy Palechor-Ceron1,2, Vera Simic1,2, Sujata Choudhury1,2, Songtao Yu1,2, Cynthia M. Simbulan-Rosenthal3, Dean Rosenthal3, Richard Schlegel1,2, Xuefeng Liu1,2
1Department of Pathology, Georgetown University Medical School, Washington, DC 20057, USA
2Center for Cell Reprogramming, Georgetown University Medical School, Washington, DC 20057, USA
3Department of Molecular and Cell Biology and Biochemistry, Georgetown University Medical School, Washington, DC 20057, USA
4Department of Biostatistics, Bioinformatics, Georgetown University Medical School, Washington, DC 20057, USA
Xuefeng Liu, email: [email protected]
Keywords: Myc, ROCK, cytoskeleton, apoptosis, telomerase
Received: May 04, 2016 Accepted: August 11, 2016 Published: August 20, 2016
The Myc/Max/Mad network plays a critical role in cell proliferation, differentiation and apoptosis and c-Myc is overexpressed in many cancers, including HPV-positive cervical cancer cell lines. Despite the tolerance of cervical cancer keratinocytes to high Myc expression, we found that the solitary transduction of the Myc gene into primary cervical and foreskin keratinocytes induced rapid cell death. These findings suggested that the anti-apoptotic activity of E7 in cervical cancer cells might be responsible for negating the apoptotic activity of over-expressed Myc. Indeed, our earlier in vitro studies demonstrated that Myc and E7 synergize in the immortalization of keratinocytes. Since we previously postulated that E7 and the ROCK inhibitor, Y-27632, were members of the same functional pathway in cell immortalization, we tested whether Y-27632 would inhibit apoptosis induced by the over-expression of Myc. Our findings indicate that Y-27632 rapidly inhibited Myc-induced membrane blebbing and cellular apoptosis and, more generally, functioned as an inhibitor of extrinsic and intrinsic pathways of cell death. Most important, Y-27632 cooperated with Myc to immortalize keratinocytes efficiently, indicating that apoptosis is a major barrier to Myc-induced immortalization of keratinocytes. The anti-apoptotic activity of Y-27632 correlated with a reduction in p53 serine 15 phosphorylation and the consequent reduction in the expression of downstream target genes p21 and DAPK1, two genes involved in the induction of cell death.
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