Lysophosphatidic acid acyltransferase-β is a prognostic marker and therapeutic target in gynecologic malignancies

Gregory M. Springett; Lynn Bonham; Amanda Hummer; Irina Linkov; Dipika Misra; Chia Ma; Gabriella Pezzoni; Stefano Di Giovine; Jack Singer; Hiroaki Kawasaki; David Spriggs; Robert Soslow; Jakob Dupont

doi:10.1158/0008-5472.CAN-05-0516

Lysophosphatidic acid acyltransferase-β is a prognostic marker and therapeutic target in gynecologic malignancies

Gregory M. Springett, Lynn Bonham, Amanda Hummer, Irina Linkov, Dipika Misra, Chia Ma, Gabriella Pezzoni, Stefano Di Giovine, Jack Singer, Hiroaki Kawasaki, David Spriggs, Robert Soslow, Jakob Dupont

Research output: Contribution to journal › Article › peer-review

51 Scopus citations

Abstract

Lysophosphatidic acid, the substrate for lysophosphatidic acid acyltransferase β (LPAAT-β), is a well-studied autocrine/paracrine signaling molecule that is secreted by ovarian cancer cells and is found at elevated levels in the blood and ascites fluid of women with ovarian cancer. LPAAT-β converts lysophosphatidic acid to phosphatidic acid, which functions as a cofactor in Akt/mTOR and Ras/Raf/Erk pathways. We report that elevated expression of LPAAT-β was associated with reduced survival in ovarian cancer and earlier progression of disease in ovarian and eradometrial cancer. Inhibition of LPAAT-β using small interfering RNA or selective inhibitors, CT32521 and CT32228, two small-molecule noncompetitive antagonists representing two different classes of chemical structures, induces apoptosis in human ovarian and endometrial cancer cell lines in vitro at pharmacologically tenable nanomolar concentrations. Inhibition of LPAAT-β also enhanced the survival of mice bearing ovarian tumor xenografts. Cytotoxicity was modulated by diacylglycerol effectors including protein kinase C and CalDAG-GEF1. LPAAT-β was localized to the endoplasmic reticulum and overexpression was associated with redistribution of protein kinase C-α. These findings identify LPAAT-β as a potential prognostic and therapeutic target in ovarian and endometrial cancer.

Original language	English
Pages (from-to)	9415-9425
Number of pages	11
Journal	Cancer Research
Volume	65
Issue number	20
DOIs	https://doi.org/10.1158/0008-5472.CAN-05-0516
State	Published - 15 Oct 2005
Externally published	Yes

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Springett, G. M., Bonham, L., Hummer, A., Linkov, I., Misra, D., Ma, C., Pezzoni, G., Di Giovine, S., Singer, J., Kawasaki, H., Spriggs, D., Soslow, R., & Dupont, J. (2005). Lysophosphatidic acid acyltransferase-β is a prognostic marker and therapeutic target in gynecologic malignancies. Cancer Research, 65(20), 9415-9425. https://doi.org/10.1158/0008-5472.CAN-05-0516

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title = "Lysophosphatidic acid acyltransferase-β is a prognostic marker and therapeutic target in gynecologic malignancies",

abstract = "Lysophosphatidic acid, the substrate for lysophosphatidic acid acyltransferase β (LPAAT-β), is a well-studied autocrine/paracrine signaling molecule that is secreted by ovarian cancer cells and is found at elevated levels in the blood and ascites fluid of women with ovarian cancer. LPAAT-β converts lysophosphatidic acid to phosphatidic acid, which functions as a cofactor in Akt/mTOR and Ras/Raf/Erk pathways. We report that elevated expression of LPAAT-β was associated with reduced survival in ovarian cancer and earlier progression of disease in ovarian and eradometrial cancer. Inhibition of LPAAT-β using small interfering RNA or selective inhibitors, CT32521 and CT32228, two small-molecule noncompetitive antagonists representing two different classes of chemical structures, induces apoptosis in human ovarian and endometrial cancer cell lines in vitro at pharmacologically tenable nanomolar concentrations. Inhibition of LPAAT-β also enhanced the survival of mice bearing ovarian tumor xenografts. Cytotoxicity was modulated by diacylglycerol effectors including protein kinase C and CalDAG-GEF1. LPAAT-β was localized to the endoplasmic reticulum and overexpression was associated with redistribution of protein kinase C-α. These findings identify LPAAT-β as a potential prognostic and therapeutic target in ovarian and endometrial cancer.",

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AU - Springett, Gregory M.

AU - Bonham, Lynn

AU - Hummer, Amanda

AU - Linkov, Irina

AU - Misra, Dipika

AU - Ma, Chia

AU - Pezzoni, Gabriella

AU - Di Giovine, Stefano

AU - Singer, Jack

AU - Kawasaki, Hiroaki

AU - Spriggs, David

AU - Soslow, Robert

AU - Dupont, Jakob

PY - 2005/10/15

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N2 - Lysophosphatidic acid, the substrate for lysophosphatidic acid acyltransferase β (LPAAT-β), is a well-studied autocrine/paracrine signaling molecule that is secreted by ovarian cancer cells and is found at elevated levels in the blood and ascites fluid of women with ovarian cancer. LPAAT-β converts lysophosphatidic acid to phosphatidic acid, which functions as a cofactor in Akt/mTOR and Ras/Raf/Erk pathways. We report that elevated expression of LPAAT-β was associated with reduced survival in ovarian cancer and earlier progression of disease in ovarian and eradometrial cancer. Inhibition of LPAAT-β using small interfering RNA or selective inhibitors, CT32521 and CT32228, two small-molecule noncompetitive antagonists representing two different classes of chemical structures, induces apoptosis in human ovarian and endometrial cancer cell lines in vitro at pharmacologically tenable nanomolar concentrations. Inhibition of LPAAT-β also enhanced the survival of mice bearing ovarian tumor xenografts. Cytotoxicity was modulated by diacylglycerol effectors including protein kinase C and CalDAG-GEF1. LPAAT-β was localized to the endoplasmic reticulum and overexpression was associated with redistribution of protein kinase C-α. These findings identify LPAAT-β as a potential prognostic and therapeutic target in ovarian and endometrial cancer.

AB - Lysophosphatidic acid, the substrate for lysophosphatidic acid acyltransferase β (LPAAT-β), is a well-studied autocrine/paracrine signaling molecule that is secreted by ovarian cancer cells and is found at elevated levels in the blood and ascites fluid of women with ovarian cancer. LPAAT-β converts lysophosphatidic acid to phosphatidic acid, which functions as a cofactor in Akt/mTOR and Ras/Raf/Erk pathways. We report that elevated expression of LPAAT-β was associated with reduced survival in ovarian cancer and earlier progression of disease in ovarian and eradometrial cancer. Inhibition of LPAAT-β using small interfering RNA or selective inhibitors, CT32521 and CT32228, two small-molecule noncompetitive antagonists representing two different classes of chemical structures, induces apoptosis in human ovarian and endometrial cancer cell lines in vitro at pharmacologically tenable nanomolar concentrations. Inhibition of LPAAT-β also enhanced the survival of mice bearing ovarian tumor xenografts. Cytotoxicity was modulated by diacylglycerol effectors including protein kinase C and CalDAG-GEF1. LPAAT-β was localized to the endoplasmic reticulum and overexpression was associated with redistribution of protein kinase C-α. These findings identify LPAAT-β as a potential prognostic and therapeutic target in ovarian and endometrial cancer.

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Lysophosphatidic acid acyltransferase-β is a prognostic marker and therapeutic target in gynecologic malignancies

Abstract

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