P73 functionally replaces p53 in Adriamycin‐treated, p53‐deficient breast cancer cells

Abstract

p53-related genes, p73 and p63, encode 2 classes of proteins, TAp73/p63 and DN-p73/p63. TA-p73/p63 demonstrate p53-like properties including gene transactivation and cell death promotion, whereas DN-p73/p63 lack these p53-like functions. Although p53-deficient cancer cells are often less responsive to chemotherapy, they are not completely drug resistant, suggesting that other apoptotic pathways are at work. Here, we compared for the first time to our knowledge p73 and p63 activation in various breast cancer (BC) cell lines after Adriamycin (ADR) treatment, an agent considered as mandatory in breast cancer chemotherapy. Our study was carried out using 1 p53-proficient BC cell line (MCF7 cells) and 3 BC cell lines deficient in p53 response (MCF7/ADR IGR , MDA-MB157 and T47D) after ADR-induced genotoxic stress. We report that in cells with no p53 response after ADR treatment, TAp73, but not TAp63 or DN-p73/p63, may replace p53 in triggering not only apoptosis but also cell cycle arrest or DNA repair effectors such as p21, GADD45, 14-3-3r and p53R2. We also demonstrate that TAp73 siRNA inhibits the accumulation of TAp73 in response to ADR treatment in MDA-MB157 cells and confers protection against ADR. ADR-induced downregulation of the DNp73 isoform in the T47D cell line with nonfunctional mutant p53 further supports anti-apoptotic function of the isoform antagonistic to both p53 and TA-p73/p63. Exogenous TAp73 and DNp73 overexpression in p53-response-deficient cell lines further confirms these results. cDNA microarray techniques demonstrated that the cellular response induced by p73 during ADR treatment could involve specific genes. ' 2005 Wiley-Liss, Inc.

Cellular immune therapy for chronic lymphocytic leukemia

“…72,73 Importantly, TAp73 can mediate apoptosis independent of functional p53 74,75 and can sensitize p53-deficient tumors to chemotherapy. [76][77][78][79] In line with these observations, we showed that the cytotoxic activity of various anticancer drugs, such as F-ara-A, was enhanced for CLL cells following CD40 ligation, particularly for CLL cells that lacked functional p53. Specific blocking of c-Abl tyrosine kinase, a kinase that stabilizes TAp73 by phosphorylation, 80,81 inhibited the capacity of CD40 ligation to induce high-level expression of TAp73 as well as Bid.…”

Combinational effects of hexane insoluble fraction of Ficus septica Burm. F. and doxorubicin chemotherapy on T47D breast cancer cells

“…Doxorubicin is a chemotherapeutic agent showing strong cytotoxic effect on T47D cell lines with IC 50 value of 15 nmol [11] . T47D cells could be resistant to doxorubicin due to p53 mutation [12,13] . Therefore, to prevent the tendency of resistence on T47D cells, combination of low concentration of doxorubicin with HIF is needed.…”

Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone

“…7). Doxorubicin inhibits cellular proliferation via p53-dependent and p53-independent mechanisms (43)(44)(45). In p53 wild-type MCF7 breast cancer cells, doxorubicin treatment causes an accumulation of p53 (45)(46)(47)(48), p53 recruits p21 (46) leading to decreased expression of cyclin B and cdc2 resulting in a cell cycle block at G 2 -M (47, 48).…”

“…However, MDA-MB-436 cells express mutated p53 and it is unlikely that increases in p53 expression seen in these tumors are capable of recruiting p21 (49). In the absence of functional p53, p73 and p63 have been shown to replace p53 inducing p21 in doxorubicintreated breast cancer cells (44), and this is a possible mechanism by which p21 accumulates following sequential administration of doxorubicin and zoledronic acid. In addition to causing a cell cycle block at G 2 -M, experiments in colon cancer cells has shown that doxorubicin can also block G 1 by reducing expression of cyclin D1 (43).…”