Unknown

Dataset Information

0

Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells.


ABSTRACT: Despite success with BRAFV600E inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. We identified a mechanism of intrinsic multidrug resistance based on the survival of a tumor cell subpopulation. Treatment with various drugs, including cisplatin and vemurafenib, uniformly leads to enrichment of slow-cycling, long-term tumor-maintaining melanoma cells expressing the H3K4-demethylase JARID1B/KDM5B/PLU-1. Proteome-profiling revealed an upregulation in enzymes of mitochondrial oxidative-ATP-synthesis (oxidative phosphorylation) in this subpopulation. Inhibition of mitochondrial respiration blocked the emergence of the JARID1B(high) subpopulation and sensitized melanoma cells to therapy, independent of their genotype. Our findings support a two-tiered approach combining anticancer agents that eliminate rapidly proliferating melanoma cells with inhibitors of the drug-resistant slow-cycling subpopulation.

SUBMITTER: Roesch A 

PROVIDER: S-EPMC3810180 | BioStudies | 2013-01-01

REPOSITORIES: biostudies

Similar Datasets

2010-01-01 | S-EPMC2882693 | BioStudies
2007-01-01 | S-EPMC2168894 | BioStudies
1000-01-01 | S-EPMC5392423 | BioStudies
2015-01-01 | S-EPMC4335723 | BioStudies
2019-01-01 | S-EPMC6411775 | BioStudies
2011-01-01 | S-EPMC3243600 | BioStudies
2013-01-01 | S-EPMC3630093 | BioStudies
2018-01-01 | S-EPMC6188148 | BioStudies
1000-01-01 | S-EPMC5731204 | BioStudies
2014-01-01 | S-EPMC4067197 | BioStudies