Transient Transfection of a Wild-Type p53 Gene Triggers Resveratrol-Induced Apoptosis in Cancer Cells

Abstract

Resveratrol is a promising chemopreventive agent that mediates many cellular targets involved in cancer signaling pathways. p53 has been suggested to play a role in the anticancer properties of resveratrol. We investigated resveratrol-induced cytotoxicity in H1299 cells, which are non-small lung cancer cells that have a partial deletion of the gene that encodes the p53 protein. The results for H1299 cells were compared with those for three cell lines that constitutively express wild-type p53: breast cancer MCF-7, adenocarcinomic alveolar basal epithelia A549 and non-small lung cancer H460. Cell viability assays revealed that resveratrol reduced the viability of all four of these cell lines in a dose- and time-dependent manner. MCF-7, A549 and H460 cells were more sensitive to resveratrol than were H1299 cells when exposed to the drug for 24 h at concentrations above 100 µM. Resveratrol also increased the p53 protein levels in MCF-7 cells without altering the p53 mRNA levels, suggesting a post-translational modulation of the protein. The resveratrol-induced cytotoxicity in these cells was partially mediated by p53 and involved the activation of caspases 9 and 7 and the cleavage of PARP. In H1299 cells, resveratrol-induced cytotoxicity was less pronounced and (in contrast to MCF-7 cells) cell death was not accompanied by caspase activation. These findings are consistent with the observation that MCF-7 cells were positively labeled by TUNEL following exposure to 100 µM resveratrol whereas H1299 cells under similar conditions were not labeled by TUNEL. The transient transfection of a wild-type p53-GFP gene caused H1299 cells to become more responsive to the pro-apoptotic properties of resveratrol, similarly to findings in the p53-positive MCF-7 cells. Our results suggest a possible therapeutic strategy based on the use of resveratrol for the treatment of tumors that are typically unresponsive to conventional therapies because of the loss of normal p53 function.

The aggregation of mutant p53 produces prion-like properties in cancer

“…93 The transient transfection of the wild-type p53-GFP gene renders H1299 (originally lacking p53) more sensitive to resveratrol and more responsive to its pro-apoptotic properties. We propose that the combined use of resveratrol and other means of keeping active p53 cells (such as gene therapy using wild-type p53 gene or chemicals to rescue the function of p53) can be used therapeutically in cancer.…”

“…We propose that the combined use of resveratrol and other means of keeping active p53 cells (such as gene therapy using wild-type p53 gene or chemicals to rescue the function of p53) can be used therapeutically in cancer. 93 Immunotherapies for amyloid proteins have been tested with promising results, leading to the development of vaccine-based clinical trials. Antibodies can disaggregate proteins, promote their extracellular degradation and block their entry into cells.…”

Resveratrol Sensitizes Lung Cancer Cell to TRAIL by p53 Independent and Suppression of Akt/NF-κB Signaling

“…4). To investigate the specific mechanism involved in resveratrol induced TRAIL-mediated apoptosis, we analyzed p53 and PUMA, both of which have been previously shown to have a potential role in apoptosis [48,[57][58][59]. Our findings demonstrate that resveratrol enhanced p53 acetylation, p53, and PUMA expression in a dose-dependent manner and was triggered by the combined treatment of resveratrol and TRAIL.…”

A Gain of Function p53 Gene Mutant Promotes Growth Suppression in Human Liver Cancer Cells

“…Cancer cells with mutated or deficient p53 have been reported to be resistant to apoptosis (Ferraz da Costa et al 2012;Rejeeth & Kannan 2014;Wang et al 2008) and this is common and an important molecular event in hepatocarcinogenesis. Therefore, replacement of the aberrant p53 gene is an attractive approach in the treatment of HCC.…”

“…Alternative strategies are by employing nonviral vectors which include naked plasmid DNA, DNA complexed with cationic lipids and particles comprising DNA condensed with cationic polymers (Ferraz da Costa et al 2012;Rejeeth & Kannan 2014;Wang et al 2008). The advantages of non-viral vectors over their viral counterparts are that they have no limitation with regard to insert-size, they are less immunogenic and they are easier to produce.…”