Delineating the role of βIV-Tubulins in pancreatic cancer: βIVb-tubulin inhibition sensitizes pancreatic cancer cells to vinca alkaloids

Sharbeen, G., McCarroll, J., Liu, J., Youkhana, J., Limbri, L.F., Biankin, A.V. , Johns, A., Kavallaris, M., Goldstein, D. and Phillips, P.A. (2016) Delineating the role of βIV-Tubulins in pancreatic cancer: βIVb-tubulin inhibition sensitizes pancreatic cancer cells to vinca alkaloids. Neoplasia, 18(12), pp. 753-764. (doi:10.1016/j.neo.2016.10.011) (PMID:27889644) (PMCID:PMC5126129)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Biankin, Professor Andrew
Authors: Sharbeen, G., McCarroll, J., Liu, J., Youkhana, J., Limbri, L.F., Biankin, A.V., Johns, A., Kavallaris, M., Goldstein, D., and Phillips, P.A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Neoplasia
Publisher:Elsevier
ISSN:1522-8002
ISSN (Online):1476-5586
Published Online:24 November 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Neoplasia 18(12):753-764
Publisher Policy:Reproduced under a Creative Commons License

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