title: Delineating the Role of βIV-Tubulins in Pancreatic Cancer: βIVb-Tubulin Inhibition Sensitizes Pancreatic Cancer Cells to Vinca Alkaloids.
abstract: Pancreatic cancer (PC) is a lethal disease which is characterized by chemoresistance. Components of the cell cytoskeleton are therapeutic targets in cancer. βIV-tubulin is one such component that has two isotypes-βIVa and βIVb. βIVa and βIVb isotypes only differ in two amino acids at their C-terminus. Studies have implicated βIVa-tubulin or βIVb-tubulin expression with chemoresistance in prostate, breast, ovarian and lung cancer. However, no studies have examined the role of βIV-tubulin in PC or attempted to identify isotype specific roles in regulating cancer cell growth and chemosensitivity. We aimed to determine the role of βIVa- or βIVb-tubulin on PC growth and chemosensitivity. PC cells (MiaPaCa-2, HPAF-II, AsPC1) were treated with siRNA (control, βIVa-tubulin or βIVb-tubulin). The ability of PC cells to form colonies in the presence or absence of chemotherapy was measured by clonogenic assays. Inhibition of βIVa-tubulin in PC cells had no effect chemosensitivity. In contrast, inhibition of βIVb-tubulin in PC cells sensitized to vinca alkaloids (Vincristine, Vinorelbine and Vinblastine), which was accompanied by increased apoptosis and enhanced cell cycle arrest. We show for the first time that βIVb-tubulin, but not βIVa-tubulin, plays a role in regulating vinca alkaloid chemosensitivity in PC cells. The results from this study suggest βIVb-tubulin may be a novel therapeutic target and predictor of vinca alkaloid sensitivity for PC and warrants further investigation.
authors.affiliation: Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales (UNSW), Sydney, Australia, 2052.
authors.forename: G
authors.initials: G
authors.lastname: Sharbeen
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia, 2031; Australian Centre for NanoMedicine, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, UNSW, Australia.
authors.forename: J
authors.initials: J
authors.lastname: McCarroll
authors.affiliation: Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales (UNSW), Sydney, Australia, 2052.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales (UNSW), Sydney, Australia, 2052.
authors.forename: J
authors.initials: J
authors.lastname: Youkhana
authors.affiliation: Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales (UNSW), Sydney, Australia, 2052.
authors.forename: L F
authors.initials: LF
authors.lastname: Limbri
authors.affiliation: The Kinghorn Cancer Centre, Cancer Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Bearsden, Glasgow, Scotland G61 1BD, United Kingdom.
authors.forename: A V
authors.initials: AV
authors.lastname: Biankin
authors.affiliation: The Kinghorn Cancer Centre, Cancer Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Johns
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, Australia, 2031; Australian Centre for NanoMedicine, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, UNSW, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Kavallaris
authors.affiliation: Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales (UNSW), Sydney, Australia, 2052.
authors.forename: D
authors.initials: D
authors.lastname: Goldstein
authors.affiliation: Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales (UNSW), Sydney, Australia, 2052; Australian Centre for NanoMedicine, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, UNSW, Australia. Electronic address: p.phillips@unsw.edu.au.
authors.forename: P A
authors.initials: PA
authors.lastname: Phillips
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D014404:Tubulin / Q000235:genetics / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology; D014748:Vinca Alkaloids / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D014404:Tubulin; D050257:Tubulin Modulators; D014748:Vinca Alkaloids