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.