- 作者: YingQi Zhou, Gang Li, Yuan Ji, Chen Liu, Jingping Zhu and Yanjun Lu
- 作者服務機構: The Third General Surgery Department, Zhanghai Hospital, Second Military Medical University, Shanghai, China
- 中文摘要: --
- 英文摘要:
Background: Studies have shown the existence of p21 induction in a p53-dependent and
-independent pathway. Our previous study indicates that DOX-induced p65 is able to bind
the p21 promoter to activate its transactivation in the cells.
Methods: Over-expression and knock-down experiments were performed in Human
Pancreatic Carcinoma (PANC1) cells. Cell cycle and cell death related proteins were
assessed by Western Blotting. Cytotoxicity assay was checked by CCK-8 kit. Cell growth
was analyzed by flow cytometers.
Results: Here we showed that over-expression of p65 decreased the cytotoxic effect of
DOX on PANC1 cells, correlating with increased induction of cytoplasmic p21. We
observed that pro-caspase-3 physically associated with cytoplasmic p21, which may be
contribution to prevent p21 translocation into the nucleus. Our data also suggested that no
clear elevation of nuclear p21 by p65 provides a survival advantage by progression cell
cycle after treatment of DOX. Likewise, down-regulation of p65 expression enhanced the
cytotoxic effect of DOX, due to a significant decrease of mRNA levels of anti-apoptotic
genes, such as the cellular inhibitor of apoptosis-1 (c-IAP1), and the long isoform of B cell
leukemia/lymphoma-2 (Bcl-2), leading to efficient induction of caspase-3 cleavage in the
cells. More, we present evidence that over-expression of p53 or p53/p65 in the PANC1
cells were more sensitive to DOX treatment, correlated with activation of caspase-3 and
clear elevation of nuclear p21 level. Our previous data suggested that expression of p21
increases Gefitinib-induced cell death by blocking the cell cycle at the G1 and G2 phases.
The present findings here reinforced this idea by showing p21’s ability of potentiality of DOX-induced cell death correlated with its inhibition of cell cycle progression after
over-expression of p53 or p53/p65.
Conclusion: Our data suggested p65 could increase p53-mediated cell death in response
to DOX in PANC1 cells. Thus, it is worth noting that in p53 null or defective tumors,
targeting in down-regulation of p65 may well be useful, leading to the potentiality of
chemotherapeutic drugs. - 中文關鍵字: --
- 英文關鍵字: p21; p65; p53; caspase-3; DOX; PANC1