Secreted protein acidic and rich in cysteine-induced cellular senescence in colorectal cancers in response to irinotecan is mediated by P53.
Cellular senescence is another mechanism that can be exploited to achieve better chemosensitivity and greater tumor regression. Unlike apoptosis, cellular senescence can be induced at much lower concentrations of chemotherapy that are better tolerated by patients. We previously revealed that secreted protein acidic and rich in cysteine (SPARC), a matricellular protein, may function as a modulator of chemotherapy sensitivity by enhancing apoptosis. Here, we examine the effects of SPARC on cellular senescence in the presence of chemotherapy. Cellular senescence is induced only in sensitive colorectal cancer (CRC) cells with low concentrations of irinotecan (CPT-11). However, CPT-11-resistant cells exposed to endogenous or exogenous SPARC can also be triggered into cellular senescence. This induction is associated with higher levels of p16(INK4A) and phosphorylated p53. Knock down of p16(INK4A) reduces drug-induced senescence in all cells, but knock down and overexpression of p53 modulates senescence only in cells exposed to SPARC. Furthermore, treatment of mice with SPARC and CPT-11 leads to significantly increased cellular senescence and tumor regression. The chemosensitizing effects of SPARC in CRCs are, therefore, probably mediated in part by activating cellular senescence.
Chan
Justin M
JM
Division of Gastroenterology, University of British Columbia, 2775 Laurel Street, Vancouver, British Columbia V5Z 1M9, Canada.
Ho
Shirley H
SH
Tai
Isabella T
IT
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D016922:Cellular Senescence / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D004249:DNA Damage; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D015676:Osteonectin / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D000972:Antineoplastic Agents, Phytogenic; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015676:Osteonectin; D016159:Tumor Suppressor Protein p53; D000077146:Irinotecan; D002166:Camptothecin