p53 acetylation enhances Taxol-induced apoptosis in human cancer cells

Abstract

Microtubule inhibitors (MTIs) such as Taxol have been used for treating various malignant tumors. Although MTIs have been known to induce cell death through mitotic arrest, other mechanisms can operate in MTI-induced cell death. Especially, the role of p53 in this process has been controversial for a long time. Here we investigated the function of p53 in Taxol-induced apoptosis using p53 wild type and p53 null cancer cell lines. p53 was upregulated upon Taxol treatment in p53 wild type cells and deletion of p53 diminished Taxol-induced apoptosis. p53 target proteins including MDM2, p21, BAX, and β-isoform of PUMA were also upregulated by Taxol in p53 wild type cells. Conversely, when the wild type p53 was re-introduced into two different p53 null cancer cell lines, Taxol-induced apoptosis was enhanced. Among post-translational modifications that affect p53 stability and function, p53 acetylation, rather than phosphorylation, increased significantly in Taxol-treated cells. When acetylation was enhanced by anti-Sirt1 siRNA or an HDAC inhibitor, Taxol-induced apoptosis was enhanced, which was not observed in p53 null cells. When an acetylation-defective mutant of p53 was re-introduced to p53 null cells, apoptosis was partially reduced compared to the re-introduction of the wild type p53. Thus, p53 plays a pro-apoptotic role in Taxol-induced apoptosis and acetylation of p53 contributes to this pro-apoptotic function in response to Taxol in several human cancer cell lines, suggesting that enhancing acetylation of p53 could have potential implication for increasing the sensitivity of cancer cells to Taxol.

Anti-Tumor Effects of the Polysaccharide Isolated from Tarphochlamys Affinis in H22 Tumor-Bearing Mice

“…p53 can also directly activate pro-apoptotic proteins such as Bax, which can also inactivate anti-apoptotic proteins such as Bcl-2 [45]. Therefore, p53 is a promising target for cancer treatment, and it has been demonstrated that up-regulating the expression of p53 is beneficial for treatment of cancers [46,47].Bcl-2 family proteins including Bax, Bcl-2 and others play pivotal roles in intrinsic apoptosis and are recognized as the first regulatory step for inducing mitochondrial apoptosis [48]. In our investigation, PTA significantly up-regulated tumor tissue expression of p53 and Bax proteins but down-regulated Bcl-2 expression.…”

The world of protein acetylation

“…In fact, acetylation appears to be essential for p53-mediated growth arrest and apoptosis [257]. Acetylation is also required for p53-mediated induction of apoptosis through HDAC-inhibitors [417] and through the microtubule inhibitor Taxol [418]. The acetylation of p53 by MOF or Tip60 on K120 is important for its activation of pro-apoptotic genes (reviewed in [419]).…”

p28-Mediated Activation of p53 in G2–M Phase of the Cell Cycle Enhances the Efficacy of DNA Damaging and Antimitotic Chemotherapy

“…DNA-damaging agents induce apoptosis in cancer cells by activating p53 through the ATM pathway (48). Taxanes also induce p53 via post-transcriptional modifications that increase both its level and activity (5). To date, strategies directed at activating p53 in tumors have largely focused on targeting wild-type p53, rather than the mutated p53 present in a significant percentage of most solid tumors.…”

“…This induces a prolonged activation of the mitotic spindle checkpoint and mitotic arrest followed by mitotic slippage and induction of apoptosis (5). Although considered cytotoxic, they are in fact cytostatic, with the arrest triggering cell death (6).…”

“…Taxanes also induce post-transcriptional acetylation and phosphorylation of p53. This increases intracellular p53, upregulating its target proteins p21 and Bax, inhibiting the cell cycle, and increasing apoptosis (5). Unfortunately, cancer cells have weak spindle checkpoints and activate various prosurvival signals that lead to clinical resistance toward taxanes.…”