Abstract
Melanoma cells can switch their phenotypes in response to microenvironmental insults. Heterogeneous melanoma populations characterized by long-term growth and a high self-renewal capacity can be obtained in vitro in EGF(+)bFGF(+) medium whilst invasive potential of melanoma cells is increased in serum-containing cultures. In the present study, we have shown that originally these patient-derived melanoma populations exhibit variable expression of pro-survival genes from the BCL-2 family and inhibitors of apoptosis (IAPs), and differ in the baseline MCL-1 transcript stability as well. While being transferred to serum-containing medium, melanoma cells are well protected from death. Immediate adaptive response of melanoma cells selectively involves a temporary MCL-1 increase, both at mRNA and protein levels, and BCL-XL can complement MCL-1, especially in MITFlow populations. Thus, the extent of MCL-1 and BCL-XL contributions seems to be cell context-dependent. An increase in MCL-1 level results from a transiently enhanced stability of its transcript, but not from altered protein turnover. Inhibition of MCL-1 preceding transfer to serum-containing medium caused the induction of cell death in a subset of melanoma cells, which confirms the involvement of MCL-1 in melanoma cell survival during the rapid alteration of growth conditions. Additionally, immediate response to serum involves the transient increase in MITF expression and inhibition of ERK-1/2 activity. Uncovering the mechanisms of adaptive response to rapid changes in microenvironment may extend our knowledge on melanoma biology, especially at the stage of dissemination.
Highlights
Phenotypic reprogramming of both normal [1,2] and to a larger extent cancer cells [3,4,5] enables them to adapt to fluctuating parameters of the microenvironment
DMBC12 and DMBC19 populations had the similar expression of microphthalmia-associated transcription factor (MITF) and MITF-dependent genes related to pigmentation, TYR and MLANA, was analyzed (Fig 1B), whereas these genes were expressed at significantly higher levels in the DMBC17 population
We have found that MCL-1 was the only pro-survival protein which was overexpressed in all melanoma populations when compared to melanocytes
Summary
Phenotypic reprogramming of both normal [1,2] and to a larger extent cancer cells [3,4,5] enables them to adapt to fluctuating parameters of the microenvironment. Epigenetic mechanisms [19,20,21] and variable activity of microphthalmia-associated transcription factor (MITF) [13,18,22,23,24,25,26,27] have been associated with interconversions of melanoma cell phenotypes. Of note, these switches may be used as soon as malignant cells encounter an appropriate microenvironment. The interaction with the tumor microenvironment could better explain the origin of melanoma cells with diverse programs, including pro-metastatic competence [13], as supported by clinical data showing that the acquisition of the ability to metastasize may occur early in melanoma development [28]
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