A vicious partnership between AKT and PHLDA3 to facilitate neuroendocrine tumors

Abstract

Neuroendocrine tumors (NETs) are rare cancers that generally have a poor prognosis. Accurate diagnosis and proper treatment of these tumors requires a better understanding of the molecular mechanisms underlying the development of NETs. It has been shown that the mTOR inhibitor everolimus can improve the progression-free survival of pancreatic NET (PanNET) patients, suggesting that inhibition of the PI3K-Akt-mTOR pathway may suppress the progression of PanNETs. PHLDA3 is a novel tumor suppressor protein that inhibits Akt activation by competition for binding to PIP₃. Our analysis of PanNETs revealed frequent loss-of-heterozygosity and DNA methylation at the PHLDA3 locus, resulting in strong suppression of PHLDA3 transcription. Such alterations in the PHLDA3 gene were also frequently found in lung NETs, suggesting the possibility that various types of NETs have in common the functional loss of the PHLDA3 gene.

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