Dataset Information

Evolution of cisplatin resistance through coordinated metabolic reprogramming of the cellular reductive state.

ABSTRACT:

Background

Cisplatin (CDDP) is a mainstay treatment for advanced head and neck squamous cell carcinomas (HNSCC) despite a high frequency of innate and acquired resistance. We hypothesised that tumours acquire CDDP resistance through an enhanced reductive state dependent on metabolic rewiring.

Methods

To validate this model and understand how an adaptive metabolic programme might be imprinted, we performed an integrated analysis of CDDP-resistant HNSCC clones from multiple genomic backgrounds by whole-exome sequencing, RNA-seq, mass spectrometry, steady state and flux metabolomics.

Results

Inactivating KEAP1 mutations or reductions in KEAP1 RNA correlated with Nrf2 activation in CDDP-resistant cells, which functionally contributed to resistance. Proteomics identified elevation of downstream Nrf2 targets and the enrichment of enzymes involved in generation of biomass and reducing equivalents, metabolism of glucose, glutathione, NAD(P), and oxoacids. This was accompanied by biochemical and metabolic evidence of an enhanced reductive state dependent on coordinated glucose and glutamine catabolism, associated with reduced energy production and proliferation, despite normal mitochondrial structure and function.

Conclusions

Our analysis identified coordinated metabolic changes associated with CDDP resistance that may provide new therapeutic avenues through targeting of these convergent pathways.

SUBMITTER: Yu W

PROVIDER: S-EPMC10205814 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Evolution of cisplatin resistance through coordinated metabolic reprogramming of the cellular reductive state.

Yu Wangie W Chen Yunyun Y Putluri Nagireddy N Osman Abdullah A Coarfa Cristian C Putluri Vasanta V Kamal Abu H M AHM Asmussen Jennifer Kay JK Katsonis Panagiotis P Myers Jeffrey N JN Lai Stephen Y SY Lu Wuhao W Stephan Clifford C CC Powell Reid T RT Johnson Faye M FM Skinner Heath D HD Kazi Jawad J Ahmed Kazi Mokim KM Hu Linghao L Threet Addison A Meyer Matthew D MD Bankson James A JA Wang Tony T Davis Jack J Parker Kirby R KR Harris Madison A MA Baek Mokryun L ML Echeverria Gloria V GV Qi Xiaoli X Wang Jin J Frederick Andy I AI Walsh Alex J AJ Lichtarge Olivier O Frederick Mitchell J MJ Sandulache Vlad C VC

British journal of cancer 20230403 11

<h4>Background</h4>Cisplatin (CDDP) is a mainstay treatment for advanced head and neck squamous cell carcinomas (HNSCC) despite a high frequency of innate and acquired resistance. We hypothesised that tumours acquire CDDP resistance through an enhanced reductive state dependent on metabolic rewiring.<h4>Methods</h4>To validate this model and understand how an adaptive metabolic programme might be imprinted, we performed an integrated analysis of CDDP-resistant HNSCC clones from multiple genomic ...[more]

PMID: 37012319

Similar Datasets

Project description:IntroductionFibroblasts are the dominant stromal cells in the gingival lamina propria with a well-established relevance in regulation of inflammation, and in innate immunity. This is exemplified by their hypersecretion of CXCL8, enhancing leukocyte infiltration in chronic and sustained inflammatory conditions. We have previously shown adenosine to be a key metabolic nucleoside that regulates stromal inflammation, but the underlying mechanisms linking adenosine to the metabolic status of fibroblasts and to the resultant inflammatory response are unclear. This study examined, by seahorse real-time cell metabolic analysis, the bioenergetics of the stromal fibroblast response to extracellular adenosine and IL-1β, focusing on CXCL8 secretion by primary human gingival fibroblasts (HGF).MethodsMarkers of the glycolytic pathway and mitochondrial biogenesis were tracked through immunoblot. Further, the influence of adenosine on mitochondrial accumulation was measured by uptake of MitoTracker Red fluorescent probe and assessment of the role of FCCP (a mitochondrial uncoupler) in CXCL8 secretion and mitochondrial accumulation.ResultsOur results show that the anti-inflammatory response of HGF to extracellular adenosine, typified by reduced CXCL8 secretion, is mediated by mitochondrial oxidative phosphorylation, reflected in higher oxygen consumption rate (OCR). In the presence of IL-1β, adenosine-treated cells induced higher ATP production, basal respiration and proton leak compared to IL-1β without adenosine. Surprisingly, adenosine had no additional effect on the IL-1β-induced higher glycolysis rate demonstrated by the extracellular acidification rate (ECAR). In addition, the higher OCR in adenosine-stimulated cells was not due to the mitochondrial fuel dependency or capacity, but due to an increase in mitochondrial biogenesis and accumulation in the cells with concomitant decrease in mitophagy-required p-PINK1 marker. We detected the accumulation of functional mitochondria with increased activation of the AMPK/SIRT1/PGC-1α pathway. The adenosine-induced uptake of MitoTracker was abrogated by PGC-1α inhibition with SR-12898. In addition, the adenosine effects on reduced CXCL8 were ablated by treatment with FCCP, a potent uncoupler of mitochondrial oxidative phosphorylation.ConclusionOur findings reveal a key role for mitochondrial bioenergetics in regulation of CXCL8-mediated inflammation by HGF through the adenosine/AMPK/SIRT1/PGC-1α axis. Therapeutically targeting this pathway in gingival fibroblasts might be a promising future strategy to modulate stromal-mediated sustained hyper-inflammatory responses.

Dataset Information

Evolution of cisplatin resistance through coordinated metabolic reprogramming of the cellular reductive state.

Background

Methods

Results

Conclusions

Publications

Evolution of cisplatin resistance through coordinated metabolic reprogramming of the cellular reductive state.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets