Overexpression of Akt converts radial growth melanoma to vertical growth melanoma

• Type of Material: Article
• Authors: Baskaran Govindarajan, Emory University; James E. Sligh, Vanderbilt University; Bethaney J. Vincent, Vanderbilt University; Meiling Li, Vanderbilt University; Jeffrey A. Canter, Vanderbilt University; Brian J. Nickoloff, Loyola University; Richard J. Rodenburg, Radboud University; Jan A. Smeitink, Radboud University; Larry Oberley, University of Iowa; Yuping Zhang, University of Iowa; Joyce Slingerland, University of Miami; Rebecca Arnold, Emory University; David J Lambeth, Emory University; Cynthia Cohen, Emory University; Lu Hilenski, Emory University; Kathy Griendling, Emory University; Marta Martinez-Diez, Universidad Autónoma de Madrid; Jose M. Cuezva, Universidad Autónoma de Madrid; Jack Arbiser, Emory University
• Language: English
• Date: 2007-03-01
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © American Society for Clinical Investigation
• Final Published Version (URL): http://www.jci.org/117/3
• Title of Journal or Parent Work: Journal of Clinical Investigation
• Volume: 117
• Issue: 3
• Start Page: 719
• End Page: 729
• Grant/Funding Information: B. Nickoloff was supported by NIH grants CA59327 and CA27502.; J.M. Cuezva was supported by grant BMC2001-0710 from the Ministerio de Ciencia y Tecnología of Spain.; B. Govindarajan was supported by a Dermatology Foundation Career Development Award.; J.L. Arbiser was supported by a Veterans Administration Merit Award, NIH grant R01 AR02030, and grants from the Jamie Rabinowitch-Davis Foundation and the Minsk Foundation.
• Research Categories: Health Sciences, Oncology

Abstract

Melanoma is the cancer with the highest increase in incidence, and transformation of radial growth to vertical growth (i.e., noninvasive to invasive) melanoma is required for invasive disease and metastasis. We have previously shown that p42/p44 MAP kinase is activated in radial growth melanoma, suggesting that further signaling events are required for vertical growth melanoma. The molecular events that accompany this transformation are not well understood. Akt, a signaling molecule downstream of PI3K, was introduced into the radial growth WM35 melanoma in order to test whether Akt overexpression is sufficient to accomplish this transformation. Overexpression of Akt led to upregulation of VEGF, increased production of superoxide ROS, and the switch to a more pronounced glycolytic metabolism. Subcutaneous implantation of WM35 cells overexpressing Akt led to rapidly growing tumors in vivo, while vector control cells did not form tumors. We demonstrated that Akt was associated with malignant transformation of melanoma through at least 2 mechanisms. First, Akt may stabilize cells with extensive mitochondrial DNA mutation, which can generate ROS. Second, Akt can induce expression of the ROS-generating enzyme NOX4. Akt thus serves as a molecular switch that increases angiogenesis and the generation of superoxide, fostering more aggressive tumor behavior. Targeting Akt and ROS may be of therapeutic importance in treatment of advanced melanoma.