The p53 Upregulated Modulator of Apoptosis (PUMA) Chemosensitizes Intrinsically Resistant Ovarian Cancer Cells to Cisplatin by Lowering the Threshold Set by Bcl-xL and Mcl-1

Abstract

Ovarian cancer is the number one cause of death from gynecologic malignancy. A defective p53 pathway is a hallmark of ovarian carcinoma. The p53 mutation correlates significantly with resistance to platinum-based chemotherapy, early relapse and shortened overall survival in ovarian cancer patients. PUMA (p53 upregulated modulator of apoptosis), a BH3-only Bcl-2 family protein, was recently identified as a transcriptional target of p53 and a potent apoptosis inducer in various cancer cells. In this study, we showed that the induction of PUMA by cisplatin was abolished in p53-deficient SKOV3 cells. Elevated expression of PUMA-induced apoptosis and sensitized A2780s and SKOV3 ovarian cancer cells to cisplatin, and the combination of PUMA and low-dose cisplatin, significantly suppressed xenograft tumor growth in vivo through enhanced induction of apoptosis compared with treatment with PUMA or cisplatin alone. The effects of PUMA were mediated by enhanced caspase activation and release of cytochrome c and Smac (second mitochondria-derived activator of caspase) into the cytosol. Furthermore, PUMA chemosensitized intrinsically resistant SKOV3 cells to cisplatin through downregulation of B-cell lymphoma-extra large (Bcl-x L ) and myeloid cell leukemia sequence 1 (Mcl-1). PUMA-mediated Bcl-x L downregulation mainly happened at the transcription level, whereas PUMA-induced Mcl-1 downregulation was associated with caspase-dependent cleavage and proteasome-mediated degradation. To our knowledge, these data suggest a new mechanism by which overexpression of PUMA enhances sensitivity of SKOV3 cells to cisplatin by lowering the threshold set simultaneously by Bcl-x L and Mcl-1. Taken together, our findings indicate that PUMA is an important modulator of therapeutic responses of ovarian cancer cells and is potentially useful as a chemosensitizer in ovarian cancer therapy.

A Novel Small-Molecule Inhibitor of Mcl-1 Blocks Pancreatic Cancer Growth In Vitro and In Vivo

“…One of the potential explanations might be the p53 status since only Capan-2 cells express wild type p53, while all other tested PC cell lines express mutated p53. Differences in p53 status might influence the efficacy of UMI-77 in Capan-2 cell line as it is known that p53 activates the transcription of Puma and Noxa, thus shifting the balance of the Bcl-2 family towards pro-apoptotic members (31–33). p53-mediated induction of Puma might enhances the sensitivity of Capan-2 cells by lowering the threshold set by Bcl-xL, which is highly expressed in these cells.…”

Defining the Molecular Signature of Chemotherapy-Mediated Lung Tumor Phenotype Modulation and Increased Susceptibility to T-Cell Killing

“…These included BBC3, which encodes PUMA, a p53 transcriptional target also involved in the response to endoplasmic reticulum stress induced by vinka alkaloids, including vinorelbine. 34,56,57 Sublethal exposure of both cell lines to cisplatin plus vinorelbine increased the expression of TFPI2, a gene encoding the protein tissue factor pathway inhibitor 2 (Fig. 4).…”

The role of ROS and subsequent DNA-damage response in PUMA-induced apoptosis of ovarian cancer cells

“…Our previous study showed that PUMA could chemosensitize ovarian cancer cells [2], However, the action mechanism remains elusive. A previous report has shown that PUMA overexpression induces ROS generation in colorectal cancer cells [26].…”