Journal
ONCOGENE
Volume 25, Issue 35, Pages 4848-4856Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1209493
Keywords
adhesion; apoptosis; collagen; ERK1/2; fibronectin; melanoma
Funding
- NIGMS NIH HHS [GM067893] Funding Source: Medline
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A hallmark feature of cancer is resistance to anoikis, apoptosis induced when cells either lose contact with or encounter an inappropriate extracellular matrix. Melanoma is inherently associated with a high degree of resistance to apoptosis. Mutations in B-RAF are prevalent in melanoma and promote constitutive MEK-ERK1/2 signaling and cell transformation. Acquisition of B-RAF mutations correlates with vertical phase growth when melanoma cells invade into the dermis, a collagen-rich environment that also contains fibronectin matrix. In addition, alterations in phosphoinositide-3 kinase (PI-3 kinase) signaling that lead to activation of AKT are detected in advanced melanomas. Here we show that knockdown of B-RAF expression by siRNA or pharmacological inhibition of MEK rendered melanoma cells susceptible to anoikis. Furthermore, adhesion to fibronectin but not collagen protected melanoma cells from anoikis through a PI-3 kinase-dependent pathway. Therefore, melanoma cells require either B-RAF or PI-3 kinase activation for protection from anoikis. Notably, AKT signaling in melanoma cells is substrate specific. These findings demonstrate that melanoma cells utilize multiple signaling pathways to provide resistance to apoptosis.
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