title: Decreased mitochondrial priming determines chemoresistance of colon cancer stem cells.
abstract: Tumor heterogeneity is in part determined by the existence of cancer stem cells (CSCs) and more differentiated tumor cells. CSCs are considered to be the tumorigenic root of cancers and suggested to be chemotherapy resistant. Here we exploited an assay that allowed us to measure chemotherapy-induced cell death in CSCs and differentiated tumor cells simultaneously. This confirmed that CSCs are selectively resistant to conventional chemotherapy, which we revealed is determined by decreased mitochondrial priming. In agreement, lowering the anti-apoptotic threshold using ABT-737 and WEHI-539 was sufficient to enhance chemotherapy efficacy, whereas ABT-199 failed to sensitize CSCs. Our data therefore point to a crucial role of BCLXL in protecting CSCs from chemotherapy and suggest that BH3 mimetics, in combination with chemotherapy, can be an efficient way to target chemotherapy-resistant CSCs.
authors.affiliation: LEXOR (Laboratory of Experimental Oncology and Radiobiology), Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Colak
authors.affiliation: LEXOR (Laboratory of Experimental Oncology and Radiobiology), Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: C D
authors.initials: CD
authors.lastname: Zimberlin
authors.affiliation: LEXOR (Laboratory of Experimental Oncology and Radiobiology), Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Fessler
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Hogdal
authors.affiliation: LEXOR (Laboratory of Experimental Oncology and Radiobiology), Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: P R
authors.initials: PR
authors.lastname: Prasetyanti
authors.affiliation: 1] LEXOR (Laboratory of Experimental Oncology and Radiobiology), Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands [2].
authors.forename: C M
authors.initials: CM
authors.lastname: Grandela
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Letai
authors.affiliation: LEXOR (Laboratory of Experimental Oncology and Radiobiology), Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: J P
authors.initials: JP
authors.lastname: Medema
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D051020:bcl-X Protein