Oncotarget

Research Papers:

βIII-Tubulin: A novel mediator of chemoresistance and metastases in pancreatic cancer

Joshua A. McCarroll, George Sharbeen, Jie Liu, Janet Youkhana, David Goldstein, Nigel McCarthy, Lydia F. Limbri, Dominic Dischl, Güralp O. Ceyhan, Mert Erkan, Amber L. Johns, Andrew V. Biankin, Maria Kavallaris and Phoebe A. Phillips _

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Oncotarget. 2015; 6:2235-2249. https://doi.org/10.18632/oncotarget.2946

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Abstract

Joshua A. McCarroll2,3,*, George Sharbeen1,*, Jie Liu1,*, Janet Youkhana1, David Goldstein1,4, Nigel McCarthy2, Lydia F. Limbri1, Dominic Dischl5, Güralp O. Ceyhan5, Mert Erkan6, Amber L. Johns7, Andrew V. Biankin7,8, Maria Kavallaris2,3 and Phoebe A. Phillips1

1 Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales (UNSW Australia), Sydney, Australia

2 Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, Australia

3 ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australian Centre for NanoMedicine, UNSW, Australia

4 Prince of Wales Hospital, Prince of Wales Clinical School, Sydney, NSW, Australia

5 Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany

6 Department of Surgery Koc University School of Medicine, Istanbul, Turkey

7 The Kinghorn Cancer Centre, Cancer Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, Australia

8 Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Bearsden, Glasgow, Scotland G61 1BD, United Kingdom

* These authors contributed equally to this work

Correspondence:

Phoebe A. Phillips, email:

Maria Kavallaris, email:

Keywords: Pancreatic cancer, chemoresistance, tumor growth, metastases, βIII-tubulin

Received: September 25, 2014 Accepted: December 09, 2014 Published: December 10, 2014

Abstract

Pancreatic cancer is a leading cause of cancer-related deaths in Western societies. This poor prognosis is due to chemotherapeutic drug resistance and metastatic spread. Evidence suggests that microtubule proteins namely, β-tubulins are dysregulated in tumor cells and are involved in regulating chemosensitivity. However, the role of β-tubulins in pancreatic cancer are unknown. We measured the expression of different β-tubulin isotypes in pancreatic adenocarcinoma tissue and pancreatic cancer cells. Next, we used RNAi to silence βIII-tubulin expression in pancreatic cancer cells, and measured cell growth in the absence and presence of chemotherapeutic drugs. Finally, we assessed the role of βIII-tubulin in regulating tumor growth and metastases using an orthotopic pancreatic cancer mouse model. We found that βIII-tubulin is highly expressed in pancreatic adenocarcinoma tissue and pancreatic cancer cells. Further, we demonstrated that silencing βIII-tubulin expression reduced pancreatic cancer cell growth and tumorigenic potential in the absence and presence of chemotherapeutic drugs. Finally, we demonstrated that suppression of βIII-tubulin reduced tumor growth and metastases in vivo. Our novel data demonstrate that βIII-tubulin is a key player in promoting pancreatic cancer growth and survival, and silencing its expression may be a potential therapeutic strategy to increase the long-term survival of pancreatic cancer patients.


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