| Theme |
Update on Pancreatic Neuroendocrine Tumors |
| Title |
PHLDA3 Determines the Destiny of Pancreatic Neuroendocrine Tumors |
| Author |
Kohei Tominaga |
Laboratory of Fundamental Oncology, National Cancer Center Research Institute / Department of Biomolecular Science, Graduate School of Science, Toho University |
| Author |
Yu Chen |
Laboratory of Fundamental Oncology, National Cancer Center Research Institute / Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University |
| Author |
Rieko Ohki |
Laboratory of Fundamental Oncology, National Cancer Center Research Institute |
| [ Summary ] |
p53 and Akt are critical players with opposing effects that regulate tumorigenesis. Akt binds to phosphatidylinositol phosphates (PIPs) in the inner plasma membrane to transmit oncogenic signals, while p53 is a pivotal tumor suppresser that activates transcription of genes involved in tumor suppression.
Our group previously reported that PHLDA3 is a p53 target gene, and encodes a pleckstrin homology (PH)-domain only protein that functions as an Akt repressor. PHLDA3 inhibits Akt activation by competitive binding to PIPs through its PH domain. In human pancreatic neuroendocrine tumors (PNETs), we demonstrated that PHLDA3 undergoes 2-hit inactivation by loss of heterozygosity (LOH) and DNA-methylation. Furthermore, we demonstrated that loss of PHLDA3 function correlates with disease progression and poor prognosis. Although an Akt pathway inhibitor everolimus is approved for the treatment of advanced PNETs, it is not yet possible to use molecular analysis to select patients who benefit from everolimus treatment. We hypothesize that patients having PNETs with loss of PHLDA3 function and hyperactivated Akt benefit from everolimus treatment, and will discuss the possibility of PHLDA3 as a novel therapeutic selection marker. |