Animal studies reveal that Akt promotes the conversion of radial growth (noninvasive) human melanoma cells to vertical growth (invasive) cells. The investigators are looking into developing drugs that block Akt and determining if they are effective for the treatment of melanoma.
Montreal - The gene Akt may be a critical new target for the management of invasive melanoma, suggest results of in vitro and animal studies.
Overexpression of this signaling molecule has been linked with transformation of melanoma from radial to vertical growth.
"Early melanoma is curable, but then it undergoes a transition from early melanoma to invasive melanoma, or radial to vertical growth melanoma," senior author Jack L. Arbiser, M.D., Ph.D., tells Dermatology Times. "It's been known for about 40 years that once melanoma gets past a certain depth and becomes vertical growth mela-noma, the prognosis gets much worse."
Identify the bad actors
"Our lab is interested in discovering which pathways make tumors bad in the hopes of coming up with small molecules that can block those pathways," Dr. Arbiser says.
"Earlier, we had found that there's a pathway called MAP kinase that's expressed in most melanomas. We found that that can change pigment cells into melanoma, but it doesn't make them very aggressive. So, we figured out that there must be something else that when you add to it, makes the melanoma very aggressive. Based on our previous studies, we found this gene Akt (to be a good candidate)."
Akt is a signaling molecule downstream of P13K. Dr. Arbiser and his colleagues inserted the Akt gene into stable WM35 radial growth phase primary human melanoma cells. Addition of this gene increased intracellular concentrations of superoxide ROS - which is believed to promote angiogenesis, mitogenesis and resistance to apoptosis in cancer cells - and increased glycolytic metabolism.
Akt kicks in overdrive
Addition of Akt also increased expression of both vascular endothelial growth factor (VEGF) and mRNA.
Nude mice implanted with WM35 cells containing the Akt gene produced tumors. In contrast, no tumors grew in mice implanted with WM35 cells that did not contain the Akt gene.
"We introduced (the Akt gene) into radial growth melanoma cells, and ... it made cells grow faster, made it generate a lot more blood vessels, and grow in mice very aggressively," Dr. Arbiser says.
The investigators demonstrate that Akt promotes malignant transformation by stabilizing cells with extensive mitochondrial DNA mutations, thus generating ROS. It also induces expression of the NOX4 enzyme, which in turn also generates ROS.
Based on these findings, Dr. Arbiser says, "We (now) have a rationale for targeting the Akt gene with new drugs. We're actively looking at drugs that inhibit this pathway. In fact, we've found a small molecule in ant venom that inhibits Akt."
Despite the fact that Akt has only shown promise as a target in animal studies, Dr. Arbiser holds high hopes that it will be identified also as a useful target for melanoma in human populations. It may also prove to be a valuable target in other cancers where Akt has been found to be elevated, including pancreatic cancer and brain tumors.