TY - JOUR
T1 - The regulatory role of aberrant Phosphatase and Tensin Homologue and Liver Kinase B1 on AKT/mTOR/c-Myc axis in pancreatic neuroendocrine tumors
AU - Chang, Tsung Ming
AU - Shan, Yan Shen
AU - Chu, Pei Yi
AU - Jiang, Shih Sheng
AU - Hung, Wen Chun
AU - Chen, Yu Lin
AU - Tu, Hsiu Chi
AU - Lin, Hui You
AU - Tsai, Hui Jen
AU - Chen, Li Tzong
N1 - Funding Information:
We are grateful for the support from the Human Biobank, Research Center of Clinical Medicine, National Cheng Kung University Hospital. This research is supported by Ministry of Science and Technology, 104-2314-B-400-012-MY3 and National Health Research Institutes, CA-105-PP-18 and CA-106-PP-18
Funding Information:
This research is supported by Ministry of Science and Technology, 104-2314-B-400-012-MY3 and National Health Research Institutes, CA-105-PP-18 and CA-106-PP-18.
Funding Information:
We are grateful for the support from the Human Biobank, Research Center of Clinical Medicine, National Cheng Kung University Hospital.
Publisher Copyright:
© Chang et al.
PY - 2017
Y1 - 2017
N2 - 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 wellknown 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 upregulation 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.
AB - 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 wellknown 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 upregulation 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.
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U2 - 10.18632/oncotarget.20956
DO - 10.18632/oncotarget.20956
M3 - Article
AN - SCOPUS:85034998571
VL - 8
SP - 98068
EP - 98083
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 58
ER -