NVP-BKM120 inhibits colon cancer growth via FoxO3a-dependent PUMA induction
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Shida Yang1, Xin Li2, Wenchang Guan3, Mingqin Qian4, Zhicheng Yao5, Xiaoxue Yin1 and Hongmei Zhao1
1Department of Laboratory Medicine, The People’s Hospital of Liaoning Province, Shenyang, China
2Department of Anesthesia, The People’s Hospital of Liaoning Province, Shenyang, China
3Department of Gynaecology and Obstetrics, The People’s Hospital of Liaoning Province, Shenyang, China
4Department of Ultrasound Diagnosis, The People’s Hospital of Liaoning Province, Shenyang, China
5Department of Neurology, The People’s Hospital of Liaoning Province, Shenyang, China
Hongmei Zhao, email: [email protected]
Keywords: NVP-BKM120, PUMA, apoptosis, FoxO3a, colon cancer
Received: May 09, 2017 Accepted: July 26, 2017 Published: September 15, 2017
NVP-BKM120, a potent and highly selective PI3K inhibitor, is currently being investigated in phase I/II clinical trials. The mechanisms of action of NVP-BKM120 in colon cancer cells are unclear. In the present study, we investigated how NVP-BKM120 suppresses colon cancer cells growth and potentiates effects of other chemotherapeutic drugs. We found that NVP-BKM120 treatment enhance PUMA induction irrespective of p53 status through the FoxO3a pathway following AKT inhibition. Furthermore, PUMA is required for NVP-BKM120-induced apoptosis in colon cancer cells. In addition, NVP-BKM120 also synergized with 5-Fluorouracil or regorafenib to induce marked apoptosis via PUMA induction. Deficiency of PUMA suppressed apoptosis and antitumor effect of NVP-BKM120 in xenograft model. These results demonstrate a key role of PUMA in mediating the anticancer effects of NVP-BKM120 and suggest that PUMA could be used as an indicator of NVP-BKM120 sensitivity, and also have important implications for it clinical applications.
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