Reciprocal regulation of MelCAM and AKT in human melanoma.
Alteration in the expression of invasion/metastasis-related melanoma cell adhesion molecule (MelCAM) is strongly associated with the acquisition of malignancy by human melanoma. However, little is known about the molecular and biochemical mechanisms that regulate the expression and function of MelCAM, or its downstream signaling transduction. In this study, we show that there is a reciprocal regulation loop between AKT and MelCAM. Pharmacological inhibition of AKT in human melanoma cell lines substantially reduced the expression of MelCAM. Overexpression of constitutively active AKT upregulated the levels of MelCAM in melanoma cell lines, whereas expression of a dominant-negative PI-3 kinase downregulated MelCAM. On the other hand, overexpression of MelCAM activated endogenous AKT and inhibited proapoptotic protein BAD in melanoma cells, leading to increased survival under stress conditions. Constitutive activation of AKT was observed in most melanoma cell lines and tumor samples of different progression stages. These data link AKT activation with MelCAM expression, and implicate that intervention of MelCAM-AKT signaling axis in melanoma is a potential therapeutical approach.
Li
Gang
G
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
Kalabis
Jiri
J
Xu
Xiaowei
X
Meier
Friedegund
F
Oka
Masahiro
M
Bogenrieder
Thomas
T
Herlyn
Meenhard
M
D000256:Adenoviridae / Q000235:genetics; D000906:Antibodies / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015703:Antigens, CD; D051929:CD146 Antigen; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002470:Cell Survival; D015536:Down-Regulation; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051025:bcl-Associated Death Protein
D000906:Antibodies; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D051929:CD146 Antigen; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases; D019006:Neural Cell Adhesion Molecules; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D051025:bcl-Associated Death Protein; C494819:BAD protein, human; C494918:AKT1 protein, human