Integrin alphav-mediated inactivation of p53 controls a MEK1-dependent melanoma cell survival pathway in three-dimensional collagen.
Integrin alphav is required for melanoma cell survival and tumor growth in various models. To elucidate integrin alphav-mediated melanoma cell survival mechanisms, we used a three-dimensional (3D) collagen gel model mimicking the pathophysiological microenvironment of malignant melanoma in the dermis. We found that integrin alphav inactivated p53 and that suppression of p53 activity by dominant negative p53 or p53-small interfering RNA obviated the need for integrin alphav for melanoma cell survival in 3D-collagen and for tumor growth in vivo. This indicates that integrin alphav-mediated inactivation of p53 functionally controls melanoma cell survival. Furthermore, we found that melanoma cell integrin alphav was required for MAPK kinase (MEK) 1 and extracellular signal-regulated kinase (ERK)1/2 activity in 3D-collagen, whereas inhibition of MEK1 activity induced apoptosis. Surprisingly, MEK1 and ERK1/2 activities were restored in integrin alphav-negative melanoma cells by suppression of p53, whereas concomitant block of MEK1 induced apoptosis. This suggests that integrin alphav controls melanoma cell survival in 3D-collagen through a pathway involving p53 regulation of MEK1 signaling.
Bao
Wenjie
W
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, 141 86, Sweden.
Strömblad
Staffan
S
D000818:Animals; D020169:Caspases / Q000378:metabolism; D018929:Cell Culture Techniques / Q000379:methods; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D020405:Dermis / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008546:Melanoma, Experimental / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D034622:RNA Interference; D012878:Skin Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D039564:Integrin alphaV; D016159:Tumor Suppressor Protein p53; D003094:Collagen; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020169:Caspases