Mcl-1 is required for melanoma cell resistance to anoikis.
Melanoma is a particularly aggressive tumor type that exhibits a high level of resistance to apoptosis. The serine/threonine kinase B-RAF is mutated in 50% to 70% of melanomas and protects melanoma cells from anoikis, a form of apoptosis induced by lack of adhesion or adhesion to an inappropriate matrix. Mutant B-RAF down-regulates two BH3-only proapoptotic proteins, Bim(EL) and Bad. BH3-only proteins act, at least in part, by sequestering prosurvival Bcl-2 family proteins and preventing them from inhibiting the mitochondrial apoptotic pathway. Several Bcl-2 proteins are up-regulated in melanoma; however, the mechanisms of up-regulation and their role in melanoma resistance to anoikis remain unclear. Using RNA interference, we show that depletion of Mcl-1 renders mutant B-RAF melanoma cells sensitive to anoikis. By contrast, minor effects were observed following depletion of either Bcl-2 or Bcl-(XL). Mcl-1 expression is enhanced in melanoma cell lines compared with melanocytes and up-regulated by the B-RAF-MEK-extracellular signal-regulated kinase 1/2 pathway through control of Mcl-1 protein turnover. Similar to B-RAF knockdown cells, adhesion to fibronectin protected Mcl-1 knockdown cells from apoptosis. Finally, expression of Bad, which does not sequester Mcl-1, further augmented apoptosis in nonadherent Mcl-1 knockdown cells. Together, these data support the notion that BH3 mimetic compounds that target Mcl-1 may be effective for the treatment of melanoma in combinatorial strategies with agents that disrupt fibronectin-integrin signaling.
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Karen
K
Boisvert-Adamo
Whitney
W
Longmate
Ethan V
EV
Abel
Andrew E
AE
Aplin
D023102:Anoikis; D002448:Cell Adhesion / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C494819:BAD protein, human; C494811:BCL2L1 protein, human; D005353:Fibronectins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases