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Horm Metab Res 2003; 35(11/12): 751-757
DOI: 10.1055/s-2004-814160
Original
© Georg Thieme Verlag Stuttgart · New York

Activation of Pro-apoptotic p38-MAPK Pathway in the Prostate Cancer Cell Line M12 Expressing a Truncated IGF-IR

J.  Wu1 , K.  Haugk2 , S.  R.  Plymate1, 2
  • 1Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA, U.S.A.
  • 2Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, U.S.A.
Further Information

Publication History

Received 28 August 2003

Accepted after Revision 22 October 2003

Publication Date:
07 January 2004 (online)

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Abstract

The type I insulin-like growth factor receptor (IGF-IR) plays a critical role in signaling survival and proliferation in many cell types. Activation of IGF-IR by its ligands promotes cell proliferation via mitogen-activated protein kinase (MAPK) cascade and cell survival via phosphoinositide 3-kinase (PI3K) cascade. The IGF-IR emerges as a powerful growth factor for many tumor cells. A truncated IGF-IR 486/STOP, described as a dominant negative IGF-IR mutant, was shown to induce apoptosis and inhibit tumor growth in vivo while endogenous IGF-IR was activated. To investigate the mechanism(s) of the action of 486/STOP, we have introduced 486/STOP into the prostate tumor model cell line M12 and its derivative M12lisn that expresses high levels of wild type IGF-IR. We have found that 486/STOP induces apoptosis in M12 and M12lisn cells in culture and that 486/STOP acts through activation of the pro-apoptotic p38-MAPK without interfering with wild type IGF-IR activation. In addition, our results have indicated that 486/STOP induced activation of p38-MAPK increases through activation of endogenous IGF-IR. These data suggest that activation of the IGF-IR by 486/STOP can selectively enhance the previously reported IGF-IR pro-apoptotic signaling pathways.

Key words

pAkt - PI3K - ERK - 486/STOP - Insulin-like Growth Factor I (IGF-I)

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S. R. Plymate, M.D.

Department of Medicine, Division of Gerontology and Geriatric Medicine · University of Washington

Box 359755 · 325 9th Ave. · Seattle · WA98104 · USA

Phone: + 1 (206) 341-5336 ·

Fax: + 1 (206) 341-5302

Email: splymate@u.washington.edu