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Molecular Medicine

, Volume 21, Issue 1, pp 466–478 | Cite as

Dual Targeting of mTOR Activity with Torin2 Potentiates Anticancer Effects of Cisplatin in Epithelial Ovarian Cancer

  • Azhar R. Hussain
  • Maha Al-Romaizan
  • Maqbool Ahmed
  • Saravanan Thangavel
  • Fouad Al-Dayel
  • Shaham Beg
  • Shahab Uddin
  • Abdul K. Siraj
  • Khawla S. Al-Kuraya
Research Article

Abstract

Mammalian target of rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K) are two key components of PI3K/Akt/mTOR signaling pathway. Dysregulation of these pathways have been found in many cancers, including epithelial ovarian cancer (EOC), however, the role of mTOR has not been fully elucidated in Middle Eastern EOC. Therefore, we investigated the activation of mTOR complexes (mTORC1 and mTORC2) in a cohort of 156 EOC from Saudi Arabia by immunohistochemistry in a tissue microarray format. mTORC1 and mTORC2 were found to be activated in 55 of 146 (37.7%) and 63 of 140 (45%) of EOC samples, respectively. mTORC1 was significantly associated with mTORC2 (p < 0.0001) activation and both mTOR complexes were significantly associated with p-AKT (p = 0.0205 and 0.0298) and p-P70S6 (p < 0.0001 and 0.0035), respectively. Interestingly, mTOR activation incurred a poor progression-free survival (PFS) (p = 0.0188) in EOC. Next, the in vitro effect of inactivation of mTOR complexes was evaluated using a second-generation mTOR inhibitor, Torin2, on a panel of EOC cell lines. Torin2 treatment decreased cell viability and induced apoptosis in a dose-dependent manner via inactivation of mTORC1 and mTORC2 and their downstream targets in EOC cell lines. Furthermore, treatment of EOC cells with a subtoxic dose of Torin2 potentiated a cisplatin-induced apoptotic response in EOC cell lines. Finally, we studied the in vivo effect of a combination of Torin2 and cisplatin and found that this combination synergistically inhibited tumor growth in nude mice. These studies highlight the importance of targeting the mTOR survival pathway and suggest that cotreatment with cisplatin and Torin2 may be beneficial for the management of EOC.

Notes

Acknowledgments

We would like to thank Roxanne Melosantos and Rafia Begum for their technical assistance and Zeeshan Qadri for statistical analysis.

Supplementary material

10020_2015_2101466_MOESM1_ESM.pdf (2.1 mb)
Supplementary material, approximately 2140 KB.

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Authors and Affiliations

  • Azhar R. Hussain
    • 1
  • Maha Al-Romaizan
    • 2
  • Maqbool Ahmed
    • 1
  • Saravanan Thangavel
    • 1
  • Fouad Al-Dayel
    • 3
  • Shaham Beg
    • 1
  • Shahab Uddin
    • 1
  • Abdul K. Siraj
    • 1
  • Khawla S. Al-Kuraya
    • 1
    • 2
  1. 1.Human Cancer Genomic Research, Research CenterKing Faisal Specialist Hospital and Research Cancer, MBC#98-16RiyadhSaudi Arabia
  2. 2.AlFaisal UniversityRiyadhSaudi Arabia
  3. 3.Department of PathologyKing Faisal Specialist Hospital and Research CenterRiyadhSaudi Arabia

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