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Lysophosphatidic acid and endothelin-induced proliferation of ovarian cancer cell lines is mitigated by neutralization of granulin–epithelin precursor (GEP), a prosurvival factor for ovarian cancer

Oncogene volume 24, pages 7084–7093 (2005)Cite this article

Abstract

Granulin-epithelin precursor (GEP/progranulin) is an autocrine growth factor for ovarian cancer. We examined the production and function of GEP and report that: (1) GEP production is regulated by endothelin (ET-1), lysophosphatidic acid (LPA), and cAMP; (2) cAMP signals GEP production through exchange protein activated by cAMP (EPAC); (3) ET-1 and cAMP/EPAC induce GEP through ERK1/2; and (4) neutralization of GEP results in apoptosis. Exposure of HEY-A8 and OVCAR3 ovarian cancer cells to LPA and ET-1 yielded GEP production and secretion in a dose- and time-dependent fashion; neither stimulated significant concentrations of cAMP directly. Stimulation of cAMP production with pertussis and cholera toxin, or forskolin induced GEP in a PKA-independent fashion. EPAC, an intracellular cAMP receptor, is activated specifically by the cAMP analog, 8-CPT-2′-O-Me-cAMP (8-CPT); 8-CPT treatment stimulated GEP production and secretion. The MEK inhibitor, U0126, abrogated GEP production in response to ET-1 and 8-CPT, confirming involvement of MAPK. A partial inhibition of basal and stimulated GEP production was observed when cells were treated with a internal calcium chelator, BAPTA. Neutralizing anti-GEP antibody reversed basal as well as LPA, ET-1 and 8-CPT-induced ovarian cancer cell growth and induced apoptosis as demonstrated by caspase-3 and PARP cleavage, DNA fragmentation, and nuclear condensation. These results indicate that GEP is a growth and survival factor for ovarian cancer, induced by LPA and ET-1 and cAMP/EPAC through ERK1/2.

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Acknowledgements

We thank L Liotta for helpful discussions and V Virador, B Taylor, S Garfield, and S Wincovitch for technical support and guidance.

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  1. Mitchell Kamrava and Fiona Simpkins: These authors contributed equally to the design, execution, and analysis of this work

Authors and Affiliations

  1. Howard Hughes Medical Institute/National Institutes of Health Research Scholars Program, National Institutes of Health, Bethesda, MD, USA

    Mitchell Kamrava, Fiona Simpkins & Emilyn Alejandro

  2. Laboratory of Pathology, Molecular Signaling Section, Center for Cancer Research, National Cancer Institute, 10 Center Drive MSC 1500, Bethesda, 20892, MD, USA

    Mitchell Kamrava, Chad Michener, Elizabeth Meltzer & Elise C Kohn

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  1. Mitchell Kamrava
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Correspondence to Elise C Kohn.

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Kamrava, M., Simpkins, F., Alejandro, E. et al. Lysophosphatidic acid and endothelin-induced proliferation of ovarian cancer cell lines is mitigated by neutralization of granulin–epithelin precursor (GEP), a prosurvival factor for ovarian cancer. Oncogene 24, 7084–7093 (2005). https://doi.org/10.1038/sj.onc.1208857

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