Oncotarget

Research Papers:

CGP57380 enhances efficacy of RAD001 in non-small cell lung cancer through abrogating mTOR inhibition-induced phosphorylation of eIF4E and activating mitochondrial apoptotic pathway

Qiuyuan Wen _, Weiyuan Wang, Jiadi Luo, Shuzhou Chu, Lingjiao Chen, Lina Xu, Hongjing Zang, Mohannad Ma Alnemah, Jian Ma and Songqing Fan

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Oncotarget. 2016; 7:27787-27801. https://doi.org/10.18632/oncotarget.8497

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Abstract

Qiuyuan Wen1, Weiyuan Wang1, Jiadi Luo1, Shuzhou Chu1, Lingjiao Chen1, Lina Xu1, Hongjing Zang1, Mohannad Ma Alnemah1, Jian Ma2, Songqing Fan1

1Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China

2Cancer Research Institute of Central South University, Changsha, Hunan, 410078, China

Correspondence to:

Songqing Fan, email: [email protected]

Keywords: non-small cell lung cancer (NSCLC), mTOR, eIF4E, Mnk1, apoptosis

Received: February 14, 2016    Accepted: March 17, 2016    Published: March 30, 2016

ABSTRACT

The mammalian target of rapamycin (mTOR) is a potentially important therapeutic target in a broad range of cancer types. mTOR inhibitors such as rapamycin and its analogs (rapalogs) have been proven effective as anticancer agents in non-small cell lung cancer (NSCLC), whereas they strongly enhance phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) and activation of Akt, which cause resistance to mTOR-targeted therapy after an initial response. Rapamycin induces eIF4E phosphorylation by activating MAPK-interacting kinases (Mnks), and therefore targeting Mnk/eIF4E pathway represents a potential therapeutic strategy for the treatment of NSCLC. Here, our results showed that over-expression of p-Mnk1 and p-eIF4E was significantly associated with poor overall survival of NSCLC patients and high expression of p-Mnk1 might act as an independent prognostic biomarker for these patients. Meanwhile, inhibiting Mnk1 expression by Mnk inhibitor (CGP57380) could abrogate rapalogs (RAD001)-induced eIF4E phosphorylation and Akt activation. Furthermore, combination of CGP57380 and RAD001 could induce NSCLC cells apoptosis via activating intrinsic mitochondrial pathway, and exert synergistic antitumor efficacy both in vitro and in vivo. In conclusion, combination of targeting both mTOR and Mnk/eIF4E signaling pathways to enhance effectiveness of mTOR-targeted cancer therapy might be significant innovation for the personalized treatment of NSCLC.


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