Overexpression of Akt converts radial growth melanoma to vertical growth melanoma

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.

Proteolipid protein 2 is associated with melanoma metastasis

“…Furthermore, the PI3K-Akt pathway is assumed to have a variety of functions in cell biology. For example, Akt converted radial growth to vertical growth in melanoma cells (10). Recently, PI3K-Akt signaling has been reported to be involved in the hepatocyte growth factorinduced migration of uveal melanoma cells (11).…”

Specifying protein kinase C functions in melanoma

“…PKCb is activated in response to oxidative stress, which is produced by UV radiation and is elevated in melanoma because of oncogene activation (e.g., BRAF) (de Souza et al, 2006;Fried and Arbiser, 2008;Govindarajan et al, 2007;Meyskens et al, 2001;Zaidi et al, 2008). Elevated reactive oxygen species (ROS) are also produced in response to PKCb activation because of the phosphorylation of p66Shc and activation of the mitochondrial permeability pore, resulting in a positive feedback involving PKCb activation and ROS generation (DelCarlo and Loeser, 2006;Giorgio et al, 2005;Pinton et al, 2007;Voris et al, 2010).…”

RGS16 Inhibits Breast Cancer Cell Growth by Mitigating Phosphatidylinositol 3-Kinase Signaling

“…Substrates of Akt include mTOR, BAD, IKK, FOXO, p27, MDM2, and GSK3␤, all of which are signaling molecules with vital functions in cell cycle regulation and growth (3). Overexpression of Akt has been shown in several tumors such as ovarian and breast carcinoma and may lead directly to transformation of malignant melanoma (5).…”