title: Irinotecan treatment and senescence failure promote the emergence of more transformed and invasive cells that depend on anti-apoptotic Mcl-1.
abstract: Induction of senescence by chemotherapy was initially characterized as a suppressive response that prevents tumor cell proliferation. However, in response to treatment, it is not really known how cells can survive senescence and how irreversible this pathway is. In this study, we analyzed cell escape in response to irinotecan, a first line treatment used in colorectal cancer that induced senescence. We detected subpopulations of cells that adapted to chemotherapy and resumed proliferation. Survival led to the emergence of more transformed cells that induced tumor formation in mice and grew in low adhesion conditions. A significant amount of viable polyploid cells was also generated following irinotecan failure. Markers such as lgr5, CD44, CD133 and ALDH were downregulated in persistent clones, indicating that survival was not associated with an increase in cancer initiating cells. Importantly, malignant cells which resisted senescence relied on survival pathways induced by Mcl-1 signaling and to a lesser extent by Bcl-xL. Depletion of Mcl-1 increased irinotecan efficiency, induced the death of polyploid cells, prevented cell emergence and inhibited growth in low-adhesion conditions. We therefore propose that Mcl-1 targeting should be considered in the future to reduce senescence escape and to improve the treatment of irinotecan-refractory colorectal cancers.
authors.affiliation: Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Jonchère
authors.affiliation: Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Vétillard
authors.affiliation: Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Toutain
authors.affiliation: Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
authors.forename: David
authors.initials: D
authors.lastname: Lam
authors.affiliation: Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
authors.forename: Anne Charlotte
authors.initials: AC
authors.lastname: Bernard
authors.affiliation: Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Henry
authors.affiliation: INSERM U892, CNRS 6299, Nantes University, Nantes, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: De Carné Trécesson
authors.affiliation: Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
authors.forename: Erick
authors.initials: E
authors.lastname: Gamelin
authors.affiliation: INSERM U892, CNRS 6299, Nantes University, Nantes, France. Gauducheau ICO Cancer Center, INSERM U892, CNRS 6299, Nantes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Juin
authors.affiliation: Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Guette
authors.affiliation: Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Coqueret
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000473:pathology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005434:Flow Cytometry; D064593:Heterografts; D006801:Humans; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D034741:RNA, Small Interfering; D000077146:Irinotecan; D002166:Camptothecin