AMPKα phosphatase Ppm1E upregulation in human gastric cancer is required for cell proliferation

// Min-Bin Chen 1, * , Yuan-Yuan Liu 1, * , Li-Bo Cheng 2, * , Jian-Wei Lu 3 , Ping Zeng 1 , Pei-Hua Lu 4 1 Department of Radiotherapy and Oncology, Kunshan First People’s Hospital Affiliated to Jiangsu University, Kunshan, China 2 Department of Ophthalmology, Wuxi Second Hospital, Nanjing Medical University, Wu'xi, China 3 Department of Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China 4 Department of Radiotherapy and Oncology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, China * These authors contributed equally to this work and co-first authors Correspondence to: Pei-Hua Lu, email: lphty1_1@163.com Keywords: gastric cancer, AMPKα, Ppm1E, mTOR, miR-135b-5p Received: January 25, 2017 Accepted: February 15, 2017 Published: March 11, 2017 ABSTRACT Activation of AMP-activated protein kinase (AMPK) is a valuable anti-cancer strategy. In the current study, we tested expression and potential function of Ca 2+ /calmodulin-dependent protein kinase phosphatase (Ppm1E), an AMPKα phosphatase, in human gastric cancers. Ppm1E expression was elevated in human gastric cancer tissues ( vs. normal tissues), which was correlated with AMPK (p-AMPKα, Thr-172) dephosphorylation and mTOR complex 1 (mTORC1) activation. Ppm1E upregulation, AMPK inhibition and mTORC1 activation were also observed in human gastric cancer cell lines (AGS, HGC-27, and SNU601). Intriguingly, Ppm1E knockdown by shRNA induced AMPK activation, mTORC1 inactivation, and proliferation inhibition in AGS cells. On the other hand, forced over-expression of Ppm1E induced further AMPK inhibition and mTORC1 activation to enhance AGS cell proliferation. Remarkably, microRNA-135b-5p (“miR-135b-5p”), an anti-Ppm1E microRNA, was downregulated in both human gastric cancer tissues and cells. Reversely, miR-135b-5p exogenous expression caused Ppm1E depletion, AMPK activation, and AGC cell proliferation inhibition. Together, Ppm1E upregulation in human gastric cancer is important for cell proliferation, possible via regulating AMPK-mTOR signaling.