A peptide inhibitor derived from p55PIK phosphatidylinositol 3-kinase regulatory subunit: A novel cancer therapy

Junbo Hu, Xianmin Xia, Aiwu Cheng, Guihua Wang, Xuelai Luo, Michael F. Reed, Tito Fojo, Alexis Oetting, Jianping Gong, Paul M. Yen

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

p55PIK, a regulatory subunit of phosphatidylinositol 3-kinase (PI3K), specifically interacts with retinoblastoma protein (Rb) through the unique NH2 terminus of p55PIK, N24. This interaction is critical for cell proliferation and cell cycle progression. To examine p55PIK as a potential target for cancer therapy, we generated an adenovirus expressing N24 (Ad-N24-GFP) and studied its effects on the proliferation of cultured cancer cells, including human colon (HT29) and thyroid (FTC236) cancer cells. Ad-N24-GFP blocked cell proliferation and induced cell cycle arrest in all cancer cell lines tested. N24 induced cell cycle arrest at G0-G 1 phase in cell lines that expressed Rb. Interestingly, N24 inhibited cell proliferation by blocking cell cycle transition at both S and G 2-M phases in FTC236 cells, which did not express Rb. When Rb was knocked down by short hairpin RNA in HT29 cells, N24 also inhibited cell cycle progression at S and G2-M phases, suggesting that p55PIK regulates cell cycle progression by Rb-dependent and Rb-independent mechanisms. Finally, Ad-N24-GFP markedly decreased the growth of xenograft tumors derived from HT29 and FTC236 cancer cells in athymic nude mice. Our data strongly suggest that N24 peptide is an effective anticancer therapy, which specifically inhibits PI3K signaling pathways mediated by p55PIK. Moreover, they show that the regulatory subunit of an enzyme, in addition to its catalytic subunit, can be an important target for drug development.

Original languageEnglish (US)
Pages (from-to)3719-3728
Number of pages10
JournalMolecular cancer therapeutics
Volume7
Issue number12
DOIs
StatePublished - Dec 1 2008

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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