Therapeutic potential of SH2 domain-containing inositol-5′-phosphatase 1 (SHIP1) and SHIP2 inhibition in cancer

Gwenny M. Fuhler, Robert Brooks, Bonnie Toms, Sonia Iyer, Elizabeth A. Gengo, Mi Young Park, Matthew Gumbleton, Dennis R. Viernes, John D. Chisholm, William G. Kerr

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Many tumors present with increased activation of the phosphatidylinositol 3-kinase (PI3K)-PtdIns(3,4,5)P 3-protein kinase B (PKB/Akt) signaling pathway. It has long been thought that the lipid phosphatases SH2 domain-containing inositol-5′-phosphatase 1 (SHIP1) and SHIP2 act as tumor suppressors by counteracting with the survival signal induced by this pathway through hydrolysis or PtdIns(3,4,5)P 3 to PtdIns(3,4)P 2. However, a growing body of evidence suggests that PtdInd(3,4)P 2 is capable of, and essential for, Akt activation, thus suggesting a potential role for SHIP1/2 enzymes as proto-oncogenes. We recently described a novel SHIP1-selective chemical inhibitor (3α-aminocholestane [3AC]) that is capable of killing malignant hematologic cells. In this study, we further investigate the biochemical consequences of 3AC treatment in multiple myeloma (MM) and demonstrate that SHIP1 inhibition arrests MM cell lines in either G0/G1 or G2/M stages of the cell cycle, leading to caspase activation and apoptosis. In addition, we show that in vivogrowth of MM cells is blocked by treatment of mice with the SHIP1 inhibitor 3AC. Furthermore, we identify three novel pan-SHIP1/2 inhibitors that efficiently kill MM cells through G2/M arrest, caspase activation and apoptosis induction. Interestingly, in SHIP2-expressing breast cancer cells that lack SHIP1 expression, pan-SHIP1/2 inhibition also reduces viable cell numbers, which can be rescued by addition of exogenous PtdIns(3,4)P 2. In conclusion, this study shows that inhibition of SHIP1 and SHIP2 may have broad clinical application in the treatment of multiple tumor types.

Original languageEnglish (US)
Pages (from-to)65-75
Number of pages11
JournalMolecular Medicine
Volume18
Issue number1
DOIs
StatePublished - Jan 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Therapeutic potential of SH2 domain-containing inositol-5′-phosphatase 1 (SHIP1) and SHIP2 inhibition in cancer'. Together they form a unique fingerprint.

  • Cite this

    Fuhler, G. M., Brooks, R., Toms, B., Iyer, S., Gengo, E. A., Park, M. Y., Gumbleton, M., Viernes, D. R., Chisholm, J. D., & Kerr, W. G. (2012). Therapeutic potential of SH2 domain-containing inositol-5′-phosphatase 1 (SHIP1) and SHIP2 inhibition in cancer. Molecular Medicine, 18(1), 65-75. https://doi.org/10.2119/molmed.2011.00178