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The mTORC2 Component Rictor Contributes to Cisplatin Resistance in Human Ovarian Cancer Cells

Cited 21 time in Web of Science Cited 27 time in Scopus
Authors
Im-aram, Akechai; Farrand, Lee; Bae, Seung-Min; Song, Gwonhwa; Song, Yong Sang; Han, Jae Yong; Tsang, Benjamin K.
Issue Date
2013
Publisher
Public Library of Science
Citation
PLoS ONE, vol.8 no.9, e75455
Description
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Resistance to cisplatin-based therapy is a major cause of treatment failure in human ovarian cancer. A better understanding of the mechanisms of cisplatin resistance will offer new insights for novel therapeutic strategies for this deadly disease. Akt and p53 are determinants of cisplatin sensitivity. Rictor is a component of mTOR protein kinase complex 2, which is required for Akt phosphorylation (Ser473) and full activation. However, the precise role of rictor and the relationship between rictor and p53 in cisplatin resistance remains poorly understood. Here, using sensitive wild-type p53 (OV2008 and A2780s), resistant wild-type p53 (C13* and OVCAR433), and p53 compromised (A2780cp, OCC1, and SKOV-3) ovarian cancer cells, we have demonstrated that (i) rictor is a determinant of cisplatin resistance in chemosensitive human ovarian cancer cells; (ii) cisplatin down-regulates rictor content by caspase-3 cleavage and proteasomal degradation; (iii) rictor down-regulation sensitizes chemo-resistant ovarian cancer cells to cisplatin-induced apoptosis in a p53-dependent manner; (iv) rictor suppresses cisplatin-induced apoptosis and confers resistance by activating and stabilizing Akt. These findings extend current knowledge on the molecular and cellular basis of cisplatin resistance and provide a rationale basis for rictor as a potential therapeutic target for chemoresistant ovarian cancer.
ISSN
1932-6203
Language
English
URI
https://hdl.handle.net/10371/100370
DOI
https://doi.org/10.1371/journal.pone.0075455
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College of Agriculture and Life Sciences (농업생명과학대학)Dept. of Food and Animal Biotechnology (식품·동물생명공학부)Journal Papers (저널논문_식품·동물생명공학부)
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