This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Madhunapantula, S. V. Articles by Robertson, G. P. Search for Related Content PubMed PubMed Citation Articles by Madhunapantula, S. V. Articles by Robertson, G. P.

PRAS40 Deregulates Apoptosis in Malignant Melanoma

Departments of ¹ Pharmacology, ² Pathology, and ³ Dermatology, The Pennsylvania State University College of Medicine; ⁴ The Foreman Foundation for Melanoma Research; and ⁵ Penn State Melanoma Therapeutics Program, Hershey, Pennsylvania

Requests for reprints: Gavin P. Robertson, Department of Pharmacology-H078, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033. Phone: 717-531-8098; Fax: 717-531-5013; E-mail: gprobertson{at}psu.edu.

Malignant melanoma is the most invasive and deadly form of skin cancer with no effective therapy to treat advanced disease, leading to poor survival rates. Akt3 signaling plays an important role in deregulating apoptosis in 70% of melanomas. Thus, targeting Akt3 signaling in melanoma patients has significant therapeutic potential for inhibiting melanomas, but no Akt3-specific chemotherapeutic agent exists. Unfortunately, nonspecific Akt inhibitors can cause systemic toxicity or increase metastasis. Identifying and targeting the Akt3 substrate that deregulates apoptosis might circumvent these complications but would require demonstration of its functional importance in disrupting normal apoptosis. In this study, PRAS40 was identified as an Akt3 substrate that deregulated apoptosis to promote melanoma tumorigenesis. Levels of phosphorylated PRAS40 (pPRAS40) increased during melanoma tumor progression paralleling increasing Akt3 activity. Majority of melanomas from patients with elevated Akt activity also had correspondingly higher levels of pPRAS40. Targeting PRAS40 or upstream Akt3 similarly reduced anchorage-independent growth in culture and inhibited tumor development in mice. Mechanistically, decreased pPRAS40 increased tumor cell apoptosis as well as sensitivity of melanoma cells to apoptosis-inducing agents, thereby decreasing chemoresistance. Collectively, these studies provide a solid mechanistic basis for targeting PRAS40 to inhibit the Akt3 signaling cascade and thereby retard melanoma development. [Cancer Res 2007;67(8):3626–36]

This article has been cited by other articles:

				A. Sharma, A. K. Sharma, S. V. Madhunapantula, D. Desai, S. J. Huh, P. Mosca, S. Amin, and G. P. Robertson Targeting Akt3 Signaling in Malignant Melanoma Using Isoselenocyanates Clin. Cancer Res., March 1, 2009; 15(5): 1674 - 1685. [Abstract] [Full Text] [PDF]

				L. Wang, T. E. Harris, and J. C. Lawrence Jr. Regulation of Proline-rich Akt Substrate of 40 kDa (PRAS40) Function by Mammalian Target of Rapamycin Complex 1 (mTORC1)-mediated Phosphorylation J. Biol. Chem., June 6, 2008; 283(23): 15619 - 15627. [Abstract] [Full Text] [PDF]

				J. A. Garcia and D. Danielpour Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies Mol. Cancer Ther., June 1, 2008; 7(6): 1347 - 1354. [Abstract] [Full Text] [PDF]

				M. A. Tran, C. D. Smith, M. Kester, and G. P. Robertson Combining Nanoliposomal Ceramide with Sorafenib Synergistically Inhibits Melanoma and Breast Cancer Cell Survival to Decrease Tumor Development Clin. Cancer Res., June 1, 2008; 14(11): 3571 - 3581. [Abstract] [Full Text] [PDF]

				M. Cheung, A. Sharma, S. V. Madhunapantula, and G. P. Robertson Akt3 and Mutant V600EB-Raf Cooperate to Promote Early Melanoma Development Cancer Res., May 1, 2008; 68(9): 3429 - 3439. [Abstract] [Full Text] [PDF]

				S. V. Madhunapantula, D. Desai, A. Sharma, S. J. Huh, S. Amin, and G. P. Robertson PBISe, a novel selenium-containing drug for the treatment of malignant melanoma Mol. Cancer Ther., May 1, 2008; 7(5): 1297 - 1308. [Abstract] [Full Text] [PDF]

				B. D. Fonseca, E. M. Smith, V. H.-Y. Lee, C. MacKintosh, and C. G. Proud PRAS40 Is a Target for Mammalian Target of Rapamycin Complex 1 and Is Required for Signaling Downstream of This Complex J. Biol. Chem., August 24, 2007; 282(34): 24514 - 24524. [Abstract] [Full Text] [PDF]