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TMX1 determines cancer cell metabolism as a thiol-based modulator of ER-mitochondria Ca2+ flux.

ABSTRACT: The flux of Ca(2+) from the endoplasmic reticulum (ER) to mitochondria regulates mitochondria metabolism. Within tumor tissue, mitochondria metabolism is frequently repressed, leading to chemotherapy resistance and increased growth of the tumor mass. Therefore, altered ER-mitochondria Ca(2+) flux could be a cancer hallmark, but only a few regulatory proteins of this mechanism are currently known. One candidate is the redox-sensitive oxidoreductase TMX1 that is enriched on the mitochondria-associated membrane (MAM), the site of ER-mitochondria Ca(2+) flux. Our findings demonstrate that cancer cells with low TMX1 exhibit increased ER Ca(2+), accelerated cytosolic Ca(2+) clearance, and reduced Ca(2+) transfer to mitochondria. Thus, low levels of TMX1 reduce ER-mitochondria contacts, shift bioenergetics away from mitochondria, and accelerate tumor growth. For its role in intracellular ER-mitochondria Ca(2+) flux, TMX1 requires its thioredoxin motif and palmitoylation to target to the MAM. As a thiol-based tumor suppressor, TMX1 increases mitochondrial ATP production and apoptosis progression.

SUBMITTER: Raturi A

PROVIDER: S-EPMC4987292 | biostudies-other | 2016 Aug

REPOSITORIES: biostudies-other

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TMX1 determines cancer cell metabolism as a thiol-based modulator of ER-mitochondria Ca2+ flux.

Raturi Arun A Gutiérrez Tomás T Ortiz-Sandoval Carolina C Ruangkittisakul Araya A Herrera-Cruz Maria Sol MS Rockley Jeremy P JP Gesson Kevin K Ourdev Dimitar D Lou Phing-How PH Lucchinetti Eliana E Tahbaz Nasser N Zaugg Michael M Baksh Shairaz S Ballanyi Klaus K Simmen Thomas T

The Journal of cell biology 20160808 4

The flux of Ca(2+) from the endoplasmic reticulum (ER) to mitochondria regulates mitochondria metabolism. Within tumor tissue, mitochondria metabolism is frequently repressed, leading to chemotherapy resistance and increased growth of the tumor mass. Therefore, altered ER-mitochondria Ca(2+) flux could be a cancer hallmark, but only a few regulatory proteins of this mechanism are currently known. One candidate is the redox-sensitive oxidoreductase TMX1 that is enriched on the mitochondria-associ ...[more]

PMID: 27502484

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Project description:Estrogens control multiple functions of hormone-responsive breast cancer cells. They regulate diverse physiological processes in various tissues through genomic and non-genomic mechanisms that result in activation or repression of gene expression. Transcription regulation upon estrogen stimulation is a critical biological process underlying the onset and progress of the majority of breast cancer. ER? requires distinct co-regulator or modulators for efficient transcriptional regulation, and they form a regulatory network. Knowing this regulatory network will enable systematic study of the effect of ER? on breast cancer.To investigate the regulatory network of ER? and discover novel modulators of ER? functions, we proposed an analytical method based on a linear regression model to identify translational modulators and their network relationships. In the network analysis, a group of specific modulator and target genes were selected according to the functionality of modulator and the ER? binding. Network formed from targets genes with ER? binding was called ER? genomic regulatory network; while network formed from targets genes without ER? binding was called ER? non-genomic regulatory network. Considering the active or repressive function of ER?, active or repressive function of a modulator, and agonist or antagonist effect of a modulator on ER?, the ER?/modulator/target relationships were categorized into 27 classes.Using the gene expression data and ER? Chip-seq data from the MCF-7 cell line, the ER? genomic/non-genomic regulatory networks were built by merging ER?/ modulator/target triplets (TF, M, T), where TF refers to the ER?, M refers to the modulator, and T refers to the target. Comparing these two networks, ER? non-genomic network has lower FDR than the genomic network. In order to validate these two networks, the same network analysis was performed in the gene expression data from the ZR-75.1 cell. The network overlap analysis between two cancer cells showed 1% overlap for the ER? genomic regulatory network, but 4% overlap for the non-genomic regulatory network.We proposed a novel approach to infer the ER?/modulator/target relationships, and construct the genomic/non-genomic regulatory networks in two cancer cells. We found that the non-genomic regulatory network is more reliable than the genomic regulatory network.

Dataset Information

TMX1 determines cancer cell metabolism as a thiol-based modulator of ER-mitochondria Ca2+ flux.

Publications

TMX1 determines cancer cell metabolism as a thiol-based modulator of ER-mitochondria Ca2+ flux.

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