Dependence on PI3K/Akt signaling for malignant rhabdoid tumor cell survival

Kristen Foster, Yong Wang, Daohong Zhou, Cynthia Wright

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Purpose: Malignant rhabdoid tumors (MRT), although rare, are one of the most aggressive pediatric malignancies. Loss of INI1, a tumor suppressor gene and member of the SWI/SNF chromatin remodeling complex, is a recurrent genetic characteristic of these tumors and an important diagnostic marker. We have previously demonstrated a novel interaction between the serine/threonine kinase Akt and INI1, as well as other SWI/SNF subunits. This, coupled with experiments in the literature suggesting that the PI3K/Akt pathway is dysregulated in MRT cells, caused us to investigate the activation and importance of this pathway in this tumor type. Methods: In this study, we used MTT assays to evaluate the sensitivity of MRT cell lines to PI3K inhibition. Western blot analysis and Raf pulldown assays were used to examine potential mechanisms of PI3K/Akt dysregulation. Results: Inhibition of the PI3K/Akt pathway caused a significant reduction in the survival of the four MRT cell lines tested, and three cell lines demonstrated constitutively active Akt. Two of these constitutively active Akt cell lines abundantly expressed IGF-1R and an inhibitor of IGF-1R, NVP-AEW541, reduced Akt phosphorylation in one of them. The third constitutively active Akt cell line appeared to express a mutant IGF-1R. Conclusions: Our data suggests that the PI3K/Akt pathway is a crucial means of maintaining the survival and growth of MRT cells. The cells therefore employ various mechanisms to stimulate this pathway, and growth factor receptor dysregulation appears to be a common method. Drugs that inhibit the PI3K pathway or interfere with IGF autocrine loops may be of great value in treating MRT, which is largely resistant to conventional chemotherapeutic approaches.

Original languageEnglish (US)
Pages (from-to)783-791
Number of pages9
JournalCancer chemotherapy and pharmacology
Volume63
Issue number5
DOIs
StatePublished - Apr 2009
Externally publishedYes

Keywords

  • Akt
  • Malignant rhabdoid tumor
  • NVP-AEW541
  • Oncogene addiction
  • PI3K
  • SWI/SNF

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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