The regulatory role of aberrant Phosphatase and Tensin Homologue and Liver Kinase B1 on AKT/mTOR/c-Myc axis in pancreatic neuroendocrine tumors

// Tsung-Ming Chang 1, * , Yan-Shen Shan 2, 3, * , Pei-Yi Chu 4, 1, 5, * , Shih Sheng Jiang 1 , Wen-Chun Hung 1 , Yu-Lin Chen 1 , Hsiu-Chi Tu 1 , Hui-You Lin 1 , Hui-Jen Tsai 1, 6, 7 and Li-Tzong Chen 1, 6, 7, 8 1 National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan 2 Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan 3 Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan 4 Department of Pathology, Show Chwan Memorial Hospital, Changhua, Taiwan 5 School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan 6 Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan 7 Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 8 Institute of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan * These authors contributed equally to this work Correspondence to: Hui-Jen Tsai, email: hjtsai@nhri.org.tw Keywords: pancreatic neuroendocrine tumor, PTEN, LKB1, mTOR, c-Myc Received: June 15, 2017      Accepted: September 03, 2017      Published: September 16, 2017 ABSTRACT Pancreatic neuroendocrine tumor (pNET) is an uncommon type of pancreatic neoplasm. Low Phosphatase and Tensin Homologue (PTEN) expression and activation of the mechanistic target of rapamycin (mTOR) pathway have been noted in pNETs, and the former is associated with poor survival in pNET patients. Based on the results of the RADIANT-3 study, everolimus, an oral mTOR inhibitor, has been approved to treat advanced pNETs. However, the exact regulatory mechanism for the mTOR pathway in pNETs remains largely unknown. PTEN and liver kinase B1 (LKB1) are well-known for their regulatory role in the mTOR pathway. We evaluated the expression of PTEN and LKB1 in 21 pNET patients, and low PTEN and LKB1 expression levels were noted in 48% and 24% of the patients, respectively. Loss of PTEN and LKB1 synergistically promoted cell proliferation of pNET, attenuated the sensitivity of cells to mTOR inhibitors and enhanced c-Myc expression, which back-regulated PTEN, AKT, mTOR and its downstream effectors. For pNET cells with low expression levels of PTEN and LKB1, silencing the expression of c-Myc by shRNA reduced their proliferative rate, while adding either c-Myc inhibitor or AMP-activated protein kinase activator reversed their resistance to mTOR inhibitors in vitro and in vivo . Furthermore, high c-Myc expression was subsequently identified in 81% of pNETs, suggesting that up-regulation of c-Myc expression in pNETs may occur through PTEN/LKB1-dependent and PTEN/LKB1-independent regulation. The results delineated the regulation of PTEN and LKB1 on the AKT/mTOR/c-Myc axis and suggested that both c-Myc and mTOR are potential therapeutic targets for pNET.