Overexpression of Akt converts radial growth melanoma to vertical growth melanoma

Baskaran Govindarajan, James E. Sligh, Bethaney J. Vincent, Meiling Li, Jeffrey A. Canter, Brian J. Nickoloff, Richard J. Rodenburg, Jan A. Smeitink, Larry Oberley, Yuping Zhang, Joyce M Slingerland, Rebecca S. Arnold, J. David Lambeth, Cynthia Cohen, Lu Hilenski, Kathy Griendling, Marta Martínez-Diez, José M. Cuezva, Jack L. Arbiser

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)719-729
Number of pages11
JournalJournal of Clinical Investigation
Volume117
Issue number3
DOIs
StatePublished - Mar 1 2007

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Melanoma
Growth
Superoxides
Neoplasms
Foster Home Care
Mitogen-Activated Protein Kinase 1
Phosphatidylinositol 3-Kinases
Mitochondrial DNA
Vascular Endothelial Growth Factor A
Up-Regulation
Neoplasm Metastasis
Mutation
Incidence
Enzymes
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Govindarajan, B., Sligh, J. E., Vincent, B. J., Li, M., Canter, J. A., Nickoloff, B. J., ... Arbiser, J. L. (2007). Overexpression of Akt converts radial growth melanoma to vertical growth melanoma. Journal of Clinical Investigation, 117(3), 719-729. https://doi.org/10.1172/JCI30102

Overexpression of Akt converts radial growth melanoma to vertical growth melanoma. / Govindarajan, Baskaran; Sligh, James E.; Vincent, Bethaney J.; Li, Meiling; Canter, Jeffrey A.; Nickoloff, Brian J.; Rodenburg, Richard J.; Smeitink, Jan A.; Oberley, Larry; Zhang, Yuping; Slingerland, Joyce M; Arnold, Rebecca S.; Lambeth, J. David; Cohen, Cynthia; Hilenski, Lu; Griendling, Kathy; Martínez-Diez, Marta; Cuezva, José M.; Arbiser, Jack L.

In: Journal of Clinical Investigation, Vol. 117, No. 3, 01.03.2007, p. 719-729.

Research output: Contribution to journalArticle

Govindarajan, B, Sligh, JE, Vincent, BJ, Li, M, Canter, JA, Nickoloff, BJ, Rodenburg, RJ, Smeitink, JA, Oberley, L, Zhang, Y, Slingerland, JM, Arnold, RS, Lambeth, JD, Cohen, C, Hilenski, L, Griendling, K, Martínez-Diez, M, Cuezva, JM & Arbiser, JL 2007, 'Overexpression of Akt converts radial growth melanoma to vertical growth melanoma', Journal of Clinical Investigation, vol. 117, no. 3, pp. 719-729. https://doi.org/10.1172/JCI30102
Govindarajan B, Sligh JE, Vincent BJ, Li M, Canter JA, Nickoloff BJ et al. Overexpression of Akt converts radial growth melanoma to vertical growth melanoma. Journal of Clinical Investigation. 2007 Mar 1;117(3):719-729. https://doi.org/10.1172/JCI30102
Govindarajan, Baskaran ; Sligh, James E. ; Vincent, Bethaney J. ; Li, Meiling ; Canter, Jeffrey A. ; Nickoloff, Brian J. ; Rodenburg, Richard J. ; Smeitink, Jan A. ; Oberley, Larry ; Zhang, Yuping ; Slingerland, Joyce M ; Arnold, Rebecca S. ; Lambeth, J. David ; Cohen, Cynthia ; Hilenski, Lu ; Griendling, Kathy ; Martínez-Diez, Marta ; Cuezva, José M. ; Arbiser, Jack L. / Overexpression of Akt converts radial growth melanoma to vertical growth melanoma. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 3. pp. 719-729.
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