Mcl-1 Is Required for Melanoma Cell Resistance to Anoikis

Abstract

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.

Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner

“…Conversely, Mcl-1 has been associated with melanoma progression 28 and shown to be critical for survival of melanoma cells undergoing ER stress 29 or anoikis 30 . Mcl-1 has also been implicated in mediating resistance of melanoma cells to radiation 31 and several chemotherapeutic agents [32][33][34] .…”

“…Melanoma is an example of tumours in which Mcl-1 plays crucial tumourpromoting roles by promoting survival on anoikis 30 and endoplasmic reticulum stress 29 and mediating resistance to radiation 31 and several anticancer agents such as Fas 32 , dacarbazine 33 contribution of these pathways to the observed upregulation of Mcl-1 in different types of tumours is not clear. In T-cell acute lymphoblastic leukaemia, follicular lymphoma, small cell lung carcinomas, ductal and colon adenocarcinoma, high Mcl-1 levels have mainly been attributed to decreased proteasomal degradation and increased stability of Mcl-1 protein 7,35 .…”

Towards personalized therapy in pediatric acute lymphoblastic leukemia: RAS mutations and prednisolone resistance

“…10 We previously showed that prednisolone down-regulates MCL1 in prednisolone-sensitive but not in prednisolone-resistant BCP-ALL cells. 11 Targeting MEK/BRAF may, therefore, act synergistically with prednisolone on the balance between pro-and anti-apoptotic proteins.…”

Down-Regulation of Mcl-1 by Small Interference RNA Induces Apoptosis and Sensitizes HL-60 Leukemia Cells to Etoposide

“…This action blocks the release of cytochrome c from the inner mitochondrial membrane space that is required for caspase activation and next apoptotic events (Warr and Shore, 2008;Zhang et al, 2012;Akagi et al, 2013). Recent studies on melanoma cells have indicated that up-regulation of Mcl-1 inhibited the death receptor pathway of apoptosis (Chetoui et al, 2008;Boisvert-Adamo et al, 2009). However, the exact role of Mcl-1 in the regulation of the extrinsic pathway of leukemic cells is not clear.…”