Division of Gastroenterology, University of British Columbia, 2775 Laurel Street, Vancouver, British Columbia V5Z 1M9, Canada.
Carcinogenesis. 2010 May;31(5):812-9. doi: 10.1093/carcin/bgq034. Epub 2010 Feb 17.
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.
细胞衰老也是一种可以利用的机制，可以提高化学敏感性和更大的肿瘤消退。与细胞凋亡不同，细胞衰老可以在化疗药物浓度低得多的情况下诱导，而患者更容易耐受。我们之前揭示了富含半胱氨酸的酸性分泌蛋白（SPARC），一种基质细胞蛋白，通过增强细胞凋亡，可能作为化疗敏感性的调节剂。在这里，我们研究了 SPARC 在化疗存在下对细胞衰老的影响。细胞衰老仅在低浓度伊立替康（CPT-11）的敏感结直肠癌（CRC）细胞中诱导。然而，暴露于内源性或外源性 SPARC 的 CPT-11 耐药细胞也可以被诱导进入细胞衰老。这种诱导与更高水平的 p16(INK4A)和磷酸化 p53 相关。p16(INK4A)的敲低减少了所有细胞中药物诱导的衰老，但 p53 的敲低和过表达仅在暴露于 SPARC 的细胞中调节衰老。此外，用 SPARC 和 CPT-11 治疗小鼠导致细胞衰老和肿瘤消退明显增加。因此，SPARC 在 CRC 中的化疗增敏作用可能部分是通过激活细胞衰老来介导的。
