Tumor cell apoptosis mediated by cytoplasmic ING1 is associated with improved survival in oral squamous cell carcinoma patients.
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Pinaki Bose1, Satbir S. Thakur2, Nigel T. Brockton3, Alexander C. Klimowicz1,4, Elizabeth Kornaga4, Steven C. Nakoneshny5, Karl T. Riabowol1,2, Joseph C. Dort5
1 Department of Oncology, University of Calgary, HRIC 2A02, 3280 Hospital Drive NW, Calgary, Alberta, Canada
2 Department of Biochemistry & Molecular Biology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada
3 Department of Population Health Research, Alberta Health Services – Cancer Care, 1403 - 29 Street NW, Calgary, Alberta, Canada
4 Functional Tissue Imaging Unit, Translational Laboratories, Tom Baker Cancer Centre, 1331 - 29 Street NW, Calgary, Alberta, Canada
5 Section of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Calgary, HRIC 2A02, 3280 Hospital Drive NW, Calgary, Alberta, Canada
Joseph C. Dort, email:
Karl T. Riabowol, email:
Keywords: Apoptosis; AQUA; head and neck squamous cell carcinoma; ING1; oral squamous cell carcinoma.
Received: February 13, 2014 Accepted: April 16, 2014 Published: April 17, 2014
The ING1 epigenetic regulator and tumor suppressor plays a central role in apoptosis. The Ing1 gene is functionally inactivated in many cancer types but is rarely mutated. Although most studies have implicated the major ING1 isoform, p33ING1b, in nuclear apoptotic signalling, we recently discovered a novel and potent apoptosis-inducing effect of p33ING1b translocation to the mitochondria in response to DNA damage. In the present study, we examined the impact of cytoplasmic/mitochondrial localization of p33ING1b in oral squamous cell carcinoma (OSCC) patient samples and explored the therapeutic potential of adenovirally-overexpressed p33ING1b in OSCC cell lines in combination with ionizing radiation (IR) treatment. In contrast with previous reports, we found that p33ING1b protein and mRNA levels are higher in OSCC compared to normal epithelial cells. In OSCC patient samples, higher levels of intra-tumoral cytoplasmic p33ING1b correlated with increased apoptotic markers and significantly better patient survival. This association was strongest in patients who received post-operative radiotherapy. IR treatment induced p33ING1b translocation to the mitochondria and adenoviral-p33ING1b synergized with IR to kill OSCC cells. Our results identify a novel functional relationship between cytoplasmic p33ING1b and patient survival and highlight the potential for the use of p33ING1b as a therapeutic agent in combination with adjuvant radiotherapy in OSCC.
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