Overexpression of Akt converts radial growth melanoma to vertical growth melanoma.
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.
Govindarajan
Baskaran
B
Department of Dermatology, Emory University School of Medicine, and Atlanta Veterans Administration Medical Center, Atlanta, Georgia 30322, USA.
Sligh
James E
JE
Vincent
Bethaney J
BJ
Li
Meiling
M
Canter
Jeffrey A
JA
Nickoloff
Brian J
BJ
Rodenburg
Richard J
RJ
Smeitink
Jan A
JA
Oberley
Larry
L
Zhang
Yuping
Y
Slingerland
Joyce
J
Arnold
Rebecca S
RS
Lambeth
J David
JD
Cohen
Cynthia
C
Hilenski
Lu
L
Griendling
Kathy
K
Martínez-Diez
Marta
M
Cuezva
José M
JM
Arbiser
Jack L
JL
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000235:genetics; D006019:Glycolysis; D006801:Humans; D008545:Melanoma / Q000098:blood supply / Q000201:enzymology / Q000473:pathology*; D008928:Mitochondria / Q000201:enzymology; D009154:Mutation; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012878:Skin Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D051057:Proto-Oncogene Proteins c-akt