Delineating the Role of betaIV-Tubulins in Pancreatic Cancer: betaIVb-Tubulin Inhibition Sensitizes Pancreatic Cancer Cells to Vinca Alkaloids
Pancreatic cancer (PC) is a lethal disease which is characterized by chemoresistance. Components of the cell cytoskeleton are therapeutic targets in cancer. betaIV-tubulin is one such component that has two isotypes-betaIVa and betaIVb. betaIVa and betaIVb isotypes only differ in two amino acids at their C-terminus. Studies have implicated betaIVa-tubulin or betaIVb-tubulin expression with chemoresistance in prostate, breast, ovarian and lung cancer. However, no studies have examined the role of betaIV-tubulin in PC or attempted to identify isotype specific roles in regulating cancer cell growth and chemosensitivity. We aimed to determine the role of betaIVa- or betaIVb-tubulin on PC growth and chemosensitivity. PC cells (MiaPaCa-2, HPAF-II, AsPC1) were treated with siRNA (control, betaIVa-tubulin or betaIVb-tubulin). The ability of PC cells to form colonies in the presence or absence of chemotherapy was measured by clonogenic assays. Inhibition of betaIVa-tubulin in PC cells had no effect chemosensitivity. In contrast, inhibition of betaIVb-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 betaIVb-tubulin, but not betaIVa-tubulin, plays a role in regulating vinca alkaloid chemosensitivity in PC cells. The results from this study suggest betaIVb-tubulin may be a novel therapeutic target and predictor of vinca alkaloid sensitivity for PC and warrants further investigation.
|ISBN||1476-5586 (Electronic) 1476-5586 (Linking)|
|Authors||Sharbeen, G.; McCarroll, J.; Liu, J.; Youkhana, J.; Limbri, L. F.; Biankin, A. V.; Johns, A.; Kavallaris, M.; Goldstein, D.; Phillips, P. A.;|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/27889644|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/13871|