title: SIRT1/PGC1α-Dependent Increase in Oxidative Phosphorylation Supports Chemotherapy Resistance of Colon Cancer.
abstract: OBJECTIVE
  Chemotherapy treatment of metastatic colon cancer ultimately fails due to development of drug resistance. Identification of chemotherapy-induced changes in tumor biology may provide insight into drug resistance mechanisms.
  
  
  METHODS
  We studied gene expression differences between groups of liver metastases that were exposed to preoperative chemotherapy or not. Multiple patient-derived colonosphere cultures were used to assess how chemotherapy alters energy metabolism by measuring mitochondrial biomass, oxygen consumption, and lactate production. Genetically manipulated colonosphere-initiated tumors were used to assess how altered energy metabolism affects chemotherapy efficacy.
  
  
  RESULTS
  Gene ontology and pathway enrichment analysis revealed significant upregulation of genes involved in oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis in metastases that were exposed to chemotherapy. This suggested chemotherapy induces a shift in tumor metabolism from glycolysis towards OXPHOS. Indeed, chemotreatment of patient-derived colonosphere cultures resulted in an increase of mitochondrial biomass, increased expression of respiratory chain enzymes, and higher rates of oxygen consumption. This was mediated by the histone deacetylase sirtuin-1 (SIRT1) and its substrate, the transcriptional coactivator PGC1α. Knockdown of SIRT1 or PGC1α prevented chemotherapy-induced OXPHOS and significantly sensitized patient-derived colonospheres as well as tumor xenografts to chemotherapy.
  
  
  CONCLUSIONS
  Chemotherapy of colorectal tumors induces a SIRT1/PGC1α-dependent increase in OXPHOS that promotes tumor survival during treatment. This phenomenon is also observed in chemotherapy-exposed resected liver metastases, strongly suggesting that chemotherapy induces long-lasting changes in tumor metabolism that potentially interfere with drug efficacy. In conclusion, we propose a novel mechanism of chemotherapy resistance that may be clinically relevant and therapeutically exploitable.
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Vellinga
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Tijana
authors.initials: T
authors.lastname: Borovski
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Vincent C J
authors.initials: VC
authors.lastname: de Boer
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Fatrai
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Susanne
authors.initials: S
authors.lastname: van Schelven
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Kari
authors.initials: K
authors.lastname: Trumpi
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Andre
authors.initials: A
authors.lastname: Verheem
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Nikol
authors.initials: N
authors.lastname: Snoeren
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Emmink
authors.affiliation: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Inne H M Borel
authors.initials: IH
authors.lastname: Rinkes
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands. o.kranenburg@umcutrecht.nl.
authors.forename: Onno
authors.initials: O
authors.lastname: Kranenburg
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004734:Energy Metabolism / Q000187:drug effects; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D056564:Sirtuin 1