title: CD95 ligand induces senescence in mismatch repair-deficient human colon cancer via chronic caspase-mediated induction of DNA damage.
abstract: CD95 is best known for its ability to induce apoptosis via a well-characterized pathway involving caspase-mediated proteolytic events. However, in apoptosis-resistant cell lines of diverse cancer types stimulation of CD95 primarily has pro-tumorigenic effects that affect many of the hallmarks of cancer. For instance, in colon cancer cells with a mutant KRAS gene CD95 primarily promotes invasion and metastasis. In the current study, we further investigated the context dependency of the consequences of CD95 activation in colon cancer. We used a series of patient-derived three-dimensional colon cancer cultures and studied their response to stimulation with CD95 ligand (CD95L). CD95L had a strong inhibitory effect on the clone-forming capacity of five out of nine cultures. In line with previous work, these cultures all had a wild-type KRAS gene and expressed high levels of CD95. Furthermore, the most sensitive cultures were characterized by microsatellite instability (MSI) and deficient mismatch repair. The reduced clonogenic growth of MSI-type colonospheres resulting from chronic CD95 stimulation was only partly due to apoptosis as many tumor cells survived treatment, yet were unable to regenerate clones. CD95 stimulation caused an irreversible cell cycle arrest, which was associated with cytokine secretion, similar to the senescence-associated secretory phenotype (SASP), and expression of senescence-associated β-galactosidase. In human colon cancer cohorts, CD95 expression was strongly correlated with the recently identified consensus molecular subtype 1 (CMS1), which mainly consists of MSI-high tumors, and with two independent SASP signatures. Mechanistically, CD95-induced senescence was caused by chronic DNA damage via caspase-activated DNAse resulting in p53 activation and p21 expression, with a minor contribution of the SASP. We conclude that induction of senescence is a hitherto unrecognized consequence of high CD95 expression, which appears to be most relevant for CMS1.
authors.affiliation: Cancer Center, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584CX, The Netherlands.
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Raats
authors.affiliation: Cancer Center, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584CX, The Netherlands.
authors.forename: Nicola
authors.initials: N
authors.lastname: Frenkel
authors.affiliation: Cancer Center, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584CX, The Netherlands.
authors.forename: Susanne J
authors.initials: SJ
authors.lastname: van Schelven
authors.affiliation: Cancer Center, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584CX, The Netherlands.
authors.forename: Inne HMBorel
authors.initials: IH
authors.lastname: Rinkes
authors.affiliation: Cancer Center, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584CX, The Netherlands.
authors.forename: Jamila
authors.initials: J
authors.lastname: Laoukili
authors.affiliation: Cancer Center, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584CX, The Netherlands.
authors.forename: Onno
authors.initials: O
authors.lastname: Kranenburg
mesh_terms: D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D053843:DNA Mismatch Repair / Q000235:genetics / Q000502:physiology*; D003851:Deoxyribonucleases / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D053842:Microsatellite Instability; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
chemical_list: C491901:FAS protein, human; D053222:Fas Ligand Protein; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D003851:Deoxyribonucleases; C109663:caspase-activated deoxyribonuclease; D001616:beta-Galactosidase; D053148:Caspase 3; D016283:Proto-Oncogene Proteins p21(ras)