Up-regulation of Mcl-1 Is Critical for Survival of Human Melanoma Cells upon Endoplasmic Reticulum Stress

Abstract

We have previously shown that most melanoma cell lines are insensitive to endoplasmic reticulum (ER) stress-induced apoptosis, and this involves activation of the mitogen-activated protein/extracellular signal-regulated kinase (MEK)/ERK signaling pathway and expression of the apoptosis repressor with caspase recruitment domain (ARC) protein in the cells. In the present study, we show that up-regulation of the antiapoptotic Bcl-2 family member Mcl-1 is another mechanism critical for protection of melanoma cells against ER stress-induced apoptosis. Inhibition of Mcl-1 by small interference RNA (siRNA) rendered melanoma cells sensitive to apoptosis induced by the ER stress inducers thapsigargin and tunicamycin, but this sensitization was partially reversed by siRNA knockdown of PUMA or Noxa, as shown in Mcl-1-deficient melanoma cells. Both PUMA and Noxa were increased by ER stress through transcriptional up-regulation, but only up-regulation of Noxa was dependent on p53, whereas up-regulation of PUMA seemed to be mediated by a p53-independent mechanism(s). Upregulation of Mcl-1 was also due to increased transcription that involved the IRE1A and activating transcription factor 6 signaling pathways of the unfolded protein response. In addition, activation of the MEK/ERK signaling pathway seemed to be necessary for optimal up-regulation of Mcl-1. Taken together, these results reveal the mechanisms of resistance of melanoma cells to apoptosis induction mediated by BH3-only proteins upon ER stress, and identify Mcl-1 as a target for the treatment of melanoma in combination with therapeutics that induce ER stress. [Cancer Res 2008;68(16):6708-17]

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] .…”

Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress

“…Quantitative real-time PCR qPCR was performed as described previously (17). The relative abundance of target mRNA in control group was arbitrarily designated as 1.…”

“…siRNA transfection was carried out as described previously (17). MIS-SION human short hairpin RNA (shRNA) lentiviral transduction particles Bim (SHCLNV-NM_009754) and the control particles were from Sigma-Aldrich.…”

“…S8B and S8C; ref. 17). As Bim transcription is responsive to ER stress (19), we tested whether ER stress was involved in upregulation of Bim by AUY922.…”

“…Multiple mechanisms such as activation of the BH3-only proteins Bim, PUMA, and Noxa, and downregulation of antiapoptotic Bcl-2 family proteins including Bcl-2 and Mcl-1 have been implicated in ER stress-induced apoptosis (17)(18)(19) We have examined the potency of the HSP90 inhibitor AUY922 in colon cancer cells with different mutational statuses of KRAS. We show here that AUY922 preferentially induces apoptosis in mutant compared with wild-type KRAS colon cancer cells, and that activation of Bim through ER stress is responsible for apoptosis triggered by AUY922.…”