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

Akechai Im-aram, Lee Farrand, Seung Min Bae, Gwonhwa Song, Yong Sang Song, Jae Yong Han, Benjamin K. Tsang

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish
Article numbere75455
JournalPLoS One
Volume8
Issue number9
DOIs
Publication statusPublished - 2013 Sep 23
Externally publishedYes

Fingerprint

cisplatin
ovarian neoplasms
Ovarian Neoplasms
Cisplatin
Cells
therapeutics
Down-Regulation
apoptosis
TOR Serine-Threonine Kinases
Apoptosis
neoplasm cells
TOR complex 2
Phosphorylation
caspase-3
Treatment Failure
Caspase 3
protein kinases
Protein Kinases
phosphorylation
Therapeutics

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Im-aram, A., Farrand, L., Bae, S. M., Song, G., Song, Y. S., Han, J. Y., & Tsang, B. K. (2013). The mTORC2 Component Rictor Contributes to Cisplatin Resistance in Human Ovarian Cancer Cells. PLoS One, 8(9), [e75455]. https://doi.org/10.1371/journal.pone.0075455

The mTORC2 Component Rictor Contributes to Cisplatin Resistance in Human Ovarian Cancer Cells. / Im-aram, Akechai; Farrand, Lee; Bae, Seung Min; Song, Gwonhwa; Song, Yong Sang; Han, Jae Yong; Tsang, Benjamin K.

In: PLoS One, Vol. 8, No. 9, e75455, 23.09.2013.

Research output: Contribution to journalArticle

Im-aram, Akechai ; Farrand, Lee ; Bae, Seung Min ; Song, Gwonhwa ; Song, Yong Sang ; Han, Jae Yong ; Tsang, Benjamin K. / The mTORC2 Component Rictor Contributes to Cisplatin Resistance in Human Ovarian Cancer Cells. In: PLoS One. 2013 ; Vol. 8, No. 9.
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