14-3-3sigma-dependent resistance to cisplatin
Han, Z.; Dimas, K.; Tian, X.; Wang, Y.; Hemmi, H.; Yamada, K.; Kato, N.; Pantazis, P.; Ramanujam, R.J.; Anant, S.; Wyche, J.H.; Houchen, C.W.
Anticancer Research 29(6): 2009-2014
2009
ISSN/ISBN: 0250-7005 PMID: 19528459 Document Number: 633393
A major factor that impedes the clinical success of cisplatin-based chemotherapy for cancer is cisplatin resistance by cancer cells. The sensitivity of parental HCT116 human colon cancer cell line and its isogenic gene-knockout sub-lines to cisplatin was determined by clonogenicity assay; furthermore, p53 activation, p21 expression, cell cycle arrest and senescence in these cells after cisplatin treatment were investigated. Parental cells were six times more resistant than 14-3-3sigma-knockout (sigma-KO) cells to cisplatin. Moreover, activation of p53, p53-dependent expression of p21 and p21-dependent senescence were observed in sigma-KO, but not parental cells after a treatment with a low cisplatin dose. A 14-3-3sigma-dependent mechanism inhibits p53 activation in parental cells treated with a low cisplatin dose, thereby blocking p21 expression that is essential for senescence and consequently conferring to the parental cells a significant degree of resistance to cisplatin.