SIRT1/PGC1α-Dependent Increase in Oxidative Phosphorylation Supports Chemotherapy Resistance of Colon Cancer

Abstract

Purpose: 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.Experimental Design: 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 patientderived 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 PGC1a. Knockdown of SIRT1 or PGC1a 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/PGC1a-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.

Molecular Portrait of Metastasis-Competent Circulating Tumor Cells in Colon Cancer Reveals the Crucial Role of Genes Regulating Energy Metabolism and DNA Repair

“…PPARGC1A is a major regulator of several key metabolic pathways and coordinates the regulation of genes promoting the conversion of glucose to fatty acids to support tumor growth (17 ). It also plays a pivotal role in inducing the expression of oxidative phosphorylation genes in various tissues, including colon cancer (18,19 ). Increased fatty acid synthesis is important in cancer (20 ).…”

miR-155 Drives Metabolic Reprogramming of ER+ Breast Cancer Cells Following Long-Term Estrogen Deprivation and Predicts Clinical Response to Aromatase Inhibitors

“…Several recent studies have reported that OXPHOS metabolism is associated with aggressiveness of cancer cells (35) and characterizes cancer cells that have developed resistance to different chemotherapeutic agents in various cancer models (36,37). Conversely, reprogramming toward a hyperglycolytic metabolism has been associated with resistance to biologic agents such as Herceptin and Avastin in breast cancer (12,38).…”

Targeting RNA helicases in cancer: The translation trap

“…This aerobic glycolysis phenomenon is often erroneously interpreted as a sign of impaired OXPHOS in cancer. In fact, increasing evidence indicates that cancer cells are reliant on mitochondria for their bioenergetic machinery and macromolecule synthesis function[68], especially when encountering cellular stressors, like chemotherapy[69], radiation therapy[70] or during metastasis[71]. It is therefore not surprising that mitochondrial respiration is being recognized as viable target for cancer therapy[68].…”