Deregulated Akt3 activity promotes development of malignant melanoma.
Malignant melanoma is the skin cancer with the most significant impact on man, carrying the highest risk of death from metastasis. Both incidence and mortality rates continue to rise each year, with no effective long-term treatment on the horizon. In part, this reflects lack of identification of critical genes involved and specific therapies targeted to correct these defects. We report that selective activation of the Akt3 protein promotes cell survival and tumor development in 43 to 60% of nonfamilial melanomas. The predominant Akt isoform active in melanomas was identified by showing that small interfering RNA (siRNA) against only Akt3, and not Akt1 or Akt2, lowered the amount of phosphorylated (active) Akt in melanoma cells. The amount of active Akt3 increased progressively during melanoma tumor progression with highest levels present in advanced-stage metastatic melanomas. Mechanisms of Akt3 deregulation occurred through a combination of overexpression of Akt3 accompanying copy number increases of the gene and decreased PTEN protein function occurring through loss or haploinsufficiency of the PTEN gene. Targeted reduction of Akt3 activity with siRNA or by expressing active PTEN protein stimulated apoptotic signaling, which reduced cell survival by increasing apoptosis rates thereby inhibiting melanoma tumor development. Identifying Akt3 as a selective target in melanoma cells provides new therapeutic opportunities for patients in the advanced stages of this disease.
Stahl
Jill M
JM
Department of Pharmacology, The Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033, USA.
Sharma
Arati
A
Cheung
Mitchell
M
Zimmerman
Melissa
M
Cheng
Jin Q
JQ
Bosenberg
Marcus W
MW
Kester
Mark
M
Sandirasegarane
Lakshman
L
Robertson
Gavin P
GP
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018450:Disease Progression; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering / Q000235:genetics; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D015513:Oncogene Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C491754:AKT3 protein, human; C491753:Akt3 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human