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

60 Citations (Scopus)

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

Fingerprint

src Homology Domains
Phosphatidylinositols
Multiple Myeloma
Neoplasms
Therapeutics
Caspases
Phosphatidylinositol 3-Kinase
Apoptosis
Inositol Polyphosphate 5-Phosphatases
Proto-Oncogene Proteins c-akt
Proto-Oncogenes
Phosphoric Monoester Hydrolases
Signal Transduction
Cell Cycle
Hydrolysis
Cell Count
Breast Neoplasms
Lipids
Cell Line

ASJC Scopus subject areas

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

Cite this

Fuhler, G. M., Brooks, R., Toms, B., Iyer, S., Gengo, E. A., Park, M. Y., ... 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

Therapeutic potential of SH2 domain-containing inositol-5′-phosphatase 1 (SHIP1) and SHIP2 inhibition in cancer. / Fuhler, Gwenny M.; Brooks, Robert; Toms, Bonnie; Iyer, Sonia; Gengo, Elizabeth A.; Park, Mi Young; Gumbleton, Matthew; Viernes, Dennis R.; Chisholm, John D; Kerr, William G.

In: Molecular Medicine, Vol. 18, No. 1, 01.2012, p. 65-75.

Research output: Contribution to journalArticle

Fuhler, GM, Brooks, R, Toms, B, Iyer, S, Gengo, EA, Park, MY, Gumbleton, M, Viernes, DR, Chisholm, JD & Kerr, WG 2012, 'Therapeutic potential of SH2 domain-containing inositol-5′-phosphatase 1 (SHIP1) and SHIP2 inhibition in cancer', Molecular Medicine, vol. 18, no. 1, pp. 65-75. https://doi.org/10.2119/molmed.2011.00178
Fuhler, Gwenny M. ; Brooks, Robert ; Toms, Bonnie ; Iyer, Sonia ; Gengo, Elizabeth A. ; Park, Mi Young ; Gumbleton, Matthew ; Viernes, Dennis R. ; Chisholm, John D ; Kerr, William G. / Therapeutic potential of SH2 domain-containing inositol-5′-phosphatase 1 (SHIP1) and SHIP2 inhibition in cancer. In: Molecular Medicine. 2012 ; Vol. 18, No. 1. pp. 65-75.
@article{c4254972c5af4e7b9650aac6ab2d1134,
title = "Therapeutic potential of SH2 domain-containing inositol-5′-phosphatase 1 (SHIP1) and SHIP2 inhibition in cancer",
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.",
author = "Fuhler, {Gwenny M.} and Robert Brooks and Bonnie Toms and Sonia Iyer and Gengo, {Elizabeth A.} and Park, {Mi Young} and Matthew Gumbleton and Viernes, {Dennis R.} and Chisholm, {John D} and Kerr, {William G.}",
year = "2012",
month = "1",
doi = "10.2119/molmed.2011.00178",
language = "English (US)",
volume = "18",
pages = "65--75",
journal = "Molecular Medicine",
issn = "1076-1551",
publisher = "Feinstein Institute for Medical Research",
number = "1",

}

TY - JOUR

T1 - Therapeutic potential of SH2 domain-containing inositol-5′-phosphatase 1 (SHIP1) and SHIP2 inhibition in cancer

AU - Fuhler, Gwenny M.

AU - Brooks, Robert

AU - Toms, Bonnie

AU - Iyer, Sonia

AU - Gengo, Elizabeth A.

AU - Park, Mi Young

AU - Gumbleton, Matthew

AU - Viernes, Dennis R.

AU - Chisholm, John D

AU - Kerr, William G.

PY - 2012/1

Y1 - 2012/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84857013000&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84857013000&partnerID=8YFLogxK

U2 - 10.2119/molmed.2011.00178

DO - 10.2119/molmed.2011.00178

M3 - Article

C2 - 22033675

AN - SCOPUS:84857013000

VL - 18

SP - 65

EP - 75

JO - Molecular Medicine

JF - Molecular Medicine

SN - 1076-1551

IS - 1

ER -