Abstract

BackgroundThe influence of the Warburg phenomenon on chemotherapy response is unknown. Saccharomyces cerevisiae mimics the Warburg effect, repressing respiration in the presence of adequate glucose. Yeast phenomic experiments were conducted to assess potential influences of Warburg metabolism on gene-drug interaction underlying the cellular response to doxorubicin. Homologous genes from yeast phenomic and cancer pharmacogenomics data were analyzed to infer evolutionary conservation of gene-drug interaction and predict therapeutic relevance.MethodsCell proliferation phenotypes (CPPs) of the yeast gene knockout/knockdown library were measured by quantitative high-throughput cell array phenotyping (Q-HTCP), treating with escalating doxorubicin concentrations under conditions of respiratory or glycolytic metabolism. Doxorubicin-gene interaction was quantified by departure of CPPs observed for the doxorubicin-treated mutant strain from that expected based on an interaction model. Recursive expectation-maximization clustering (REMc) and Gene Ontology (GO)-based analyses of interactions identified functional biological modules that differentially buffer or promote doxorubicin cytotoxicity with respect to Warburg metabolism. Yeast phenomic and cancer pharmacogenomics data were integrated to predict differential gene expression causally influencing doxorubicin anti-tumor efficacy.ResultsYeast compromised for genes functioning in chromatin organization, and several other cellular processes are more resistant to doxorubicin under glycolytic conditions. Thus, the Warburg transition appears to alleviate requirements for cellular functions that buffer doxorubicin cytotoxicity in a respiratory context. We analyzed human homologs of yeast genes exhibiting gene-doxorubicin interaction in cancer pharmacogenomics data to predict causality for differential gene expression associated with doxorubicin cytotoxicity in cancer cells. This analysis suggested conserved cellular responses to doxorubicin due to influences of homologous recombination, sphingolipid homeostasis, telomere tethering at nuclear periphery, actin cortical patch localization, and other gene functions.ConclusionsWarburg status alters the genetic network required for yeast to buffer doxorubicin toxicity. Integration of yeast phenomic and cancer pharmacogenomics data suggests evolutionary conservation of gene-drug interaction networks and provides a new experimental approach to model their influence on chemotherapy response. Thus, yeast phenomic models could aid the development of precision oncology algorithms to predict efficacious cytotoxic drugs for cancer, based on genetic and metabolic profiles of individual tumors.

Highlights

  • The influence of the Warburg phenomenon on chemotherapy response is unknown

  • In a respiratory or glycolytic (HLEG or HLD media, respectively) context (Fig. 1a), quantitative high-throughput cell array phenotyping (Q-HTCP) technology was used for high throughput kinetic imaging of 384-culture cell arrays plated on agar media (Fig. 1b), image analysis (Fig. 1c), and growth curve fitting (Fig. 1d) to obtain the cell proliferation parameters (CPPs), L, K, and r [28, 31, 33], which were used to measure doxorubicin-gene interaction across the entire yeast knockout and knockdown (YKO/KD) library

  • Recursive expectation-maximization clustering (REMc) and Gene Ontology Term Averaging (GTA) reveal genetic modules that buffer doxorubicin, and how they are influenced by Warburg metabolism (Fig. 1h)

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Summary

Introduction

The influence of the Warburg phenomenon on chemotherapy response is unknown. Saccharomyces cerevisiae mimics the Warburg effect, repressing respiration in the presence of adequate glucose. Topoisomerase II is an ATP-dependent enzyme that relieves the DNA torsional stress occurring with replication or transcription by catalyzing a double-stranded DNA (dsDNA) break, relaxing positive and negative DNA supercoiling, and re-ligating the DNA [14] Inhibiting this activity can result in irreparable DNA damage and induction of apoptosis, selectively killing rapidly dividing proliferating cells [15,16,17]. In addition to its potent anti-cancer therapeutic properties, doxorubicin is known for dose-limiting cardiomyocyte toxicity, causing cardiomyopathy and heart failure years post-treatment [21]. In this regard, topoisomerase IIB is highly expressed in myocardiocytes, where tissue-specific deletion suppresses cardiac toxicity in mice [22]. A detailed understanding of drug-gene interaction could advance the rationale for more precisely prescribing doxorubicin (among other cytotoxic agents) and predicting toxicity, based on the unique genetic context of each patient’s tumor genetic profile as well as germline functional variation

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