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, Yan Shen Shan, Pei Yi Chu, Shih Sheng Jiang, Wen Chun Hung, Yu Lin Chen, Hsiu Chi Tu, Hui You Lin, Hui Jen Tsai, Li Tzong Chen

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3 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)98068-98083
Number of pages16
JournalOncotarget
Volume8
Issue number58
DOIs
Publication statusPublished - 2017

All Science Journal Classification (ASJC) codes

  • Oncology

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    Chang, T. M., Shan, Y. S., Chu, P. Y., Jiang, S. S., Hung, W. C., Chen, Y. L., Tu, H. C., Lin, H. Y., Tsai, H. J., & Chen, L. T. (2017). The regulatory role of aberrant Phosphatase and Tensin Homologue and Liver Kinase B1 on AKT/mTOR/c-Myc axis in pancreatic neuroendocrine tumors. Oncotarget, 8(58), 98068-98083. https://doi.org/10.18632/oncotarget.20956