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Thioridazine upregulates programmed cell death 4 to induce apoptosis in nasopharyngeal carcinoma through the PI3K/Akt signalling pathway

Liu, Jinkuna,*; Ying, Minb,*; Zhang, Junyic,*; Tu, Weid; Zeng, Chaod; Wu, Bina; Wang, Qina; Shen, Hongguid; Zhu, Zhiboc; Cai, Hongbingc

doi: 10.1097/CAD.0000000000000574
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Thioridazine (THZ) has been identified as a potential regulator of tumour progression, and programmed cell death 4 (PDCD4) has been reported as a novel tumour suppressor. This study aimed to investigate the link between PDCD4 and THZ in the regulation of nasopharyngeal cancer (NPC) cell proliferation. The effect of THZ on NPC cells was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays. Then, the involvement of apoptosis and cell cycle in the THZ-mediated regulation of cell viability was assessed by flow cytometry. Related mRNAs and proteins were subsequently examined by real-time PCR and western blot, respectively. After transfection with the PDCD4-siRNA, pGC-FU-GFP-PDCD4 vector and phosphoinositide 3-kinase (PI3K) inhibitor Ly294002, we investigated the antagonistic effects of THZ and PDCD4 on NPC-related protein expression. MTT assays showed that THZ treatment suppressed cell viability. THZ-treated cells were arrested at the G1/G0 phase and showed a significantly increased apoptotic fraction. Furthermore, PDCD4-siRNA antagonized THZ treatment and promoted NPC cell proliferation. Western blot analysis showed that PDCD4 overexpression or PI3K inhibition by LY294002 significantly reduced the expression of phospho-PI3K, phospho-Akt, phospho-mammalian target of rapamycin and phospho-p70s6k, but not their total protein levels. In conclusion, our findings show that THZ and PDCD4 exert antagonistic effects on NPC cell proliferation, probably through the PI3K/Akt pathway. Moreover, these results provide an insight into the mechanism by which THZ targets PDCD4 in NPC cell lines and suggest that the ectopic expression of PDCD4 is a potential therapeutic strategy.

aBasic Research Laboratory, Chongqing Hospital of Traditional Chinese Medicine

bDepartment of Radiation Oncology, Chongqing Cancer Institute and Hospital and Cancer Center, Chongqing

cDepartment of Oncology, TCM-Integrated Cancer Center

dSchool of Traditional Chinese Medicine, Southern Medical University, Guangzhou, People’s Republic of China

* Jinkun Liu, Min Ying and Junyi Zhang contributed equally to the writing of this article.

Correspondence to Hongbing Cai, PhD, TCM-Integrated Cancer Center, Southern Medical University, Guangzhou 510000, People’s Republic of China Tel/fax: +86 236 763 3702; e-mail: zhiyin666666@126.com

Received October 22, 2016

Accepted October 25, 2017

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