Disruption of p53 in human cancer cells alters the responses to therapeutic agents

5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

“…37 According to the literature, 5-FU and its metabolites have several direct or indirect target points within cells, including DNA, RNA and ribosomal biogenesis. 1,4,38 Although DNA lesion represent the most well-documented incident causing activation of p53, recent reports also involve transcriptional stress and ribosome damage in signaling events, leading to specific posttranslational modifications of the tumor suppressor. 5,34 An accumulation of double-strand breaks in response to 5-FU in HCT116 cells is evident as the number of gH2AX foci observed by immunostaining increased over time (data not shown), but our data involving ATM inhibition by KU55933 and Chk2-deficient cells excluded the DNA damage response as a starting point for Ca 2 þ -induced p53 phospho activation.…”

“…As a consequence of a depleted thymine pool, forced incorporation of uracil and subsequent impairment of DNA replication and repair may then trigger activation of specific cell death pathways. 1 It has also been suggested that loss of carcinogenic properties in colon and breast cancer cell lines may be caused by RNA stress through misincorporation of fluorouridine triphosphate, [2][3][4] thus inhibiting processes such as rRNA maturation, splicing of pre-mRNA and post-transcriptional modification of tRNAs. 1 In comparison with the generally accepted ATM (kinase ataxia telangiectasia mutated)/ATR (Rad3-related protein)-Chk1/Chk2 (checkpoint kinases 1 and 2, respectively)-p53 signaling pathway, leading to apoptotic cell death in response to severe DNA damage, significantly less has been reported regarding death signaling cascades originating from RNA damage, even though it has been proposed that transcriptional stress also can lead to p53 activation.…”

The Angiogenic Switch Molecule, Secreted FGF-Binding Protein, an Indicator of Early Stages of Pancreatic and Colorectal Adenocarcinoma

“…Disruption of p53 by gene targeting in human colon cancer cells results in cell resistance to different chemotherapeutic agents, as opposed to wild type cells (35). Hence, loss of p53 in human colorectal cancers may explain the inefficacy of chemotherapy and may be correlated with decreased survival in patients with colorectal adenocarcinomas (36)(37)(38)(39).…”

Methylation-induced silencing of ASC and the effect of expressed ASC on p53-mediated chemosensitivity in colorectal cancer

“…Several clinical and experimental trials have shown the inactivation of p53 to be correlated with resistance to chemotherapy in colorectal cancers (Lowe et al, 1994;Bunz et al, 1999). p53 is a transcriptional factor, which induces its target genes, such as p21, Bax, Noxa, and Puma, to regulate either cell cycle arrest or apoptosis in response to chemotherapeutic drugs (el-Deiry et al, 1993;Miyashita and Reed, 1995;Vogelstein et al, 2000;Oda et al, 2000;Yu et al, 2003).…”

“…We next used HCT116 colon cancer cell lines with or without wild-type 53, which were generous gifts from Dr B Vogelstein at Johns Hopkins University (Bunz et al, 1999), to confirm the role of ASC in p53-dependent chemosensitivity. As shown in Figure 3a and b, HCT116 cells had no trace of ASC expression regardless of p53 status.…”