Journal Article

Secreted protein acidic and rich in cysteine-induced cellular senescence in colorectal cancers in response to irinotecan is mediated by P53

Justin M. Chan, Shirley H. Ho and Isabella T. Tai

in Carcinogenesis

Volume 31, issue 5, pages 812-819
Published in print May 2010 | ISSN: 0143-3334
Published online February 2010 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgq034
Secreted protein acidic and rich in cysteine-induced cellular senescence in colorectal cancers in response to irinotecan is mediated by P53

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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 p16INK4A and phosphorylated p53. Knock down of p16INK4A 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.

Journal Article.  6266 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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