Antitumor activity of curcumin is involved in down-regulation of YAP/TAZ expression in pancreatic cancer cells

Abstract

Pancreatic cancer (PC) is one of the most aggressive human malignancies worldwide and is the fourth leading cause of cancer-related deaths. Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant. Certain studies have demonstrated that curcumin exerts its anti-tumor function in a variety of human cancers including PC, via targeting multiple therapeutically important cancer signaling pathways. However, the detailed molecular mechanisms are not fully understood. Two transcriptional co-activators, YAP (Yes-associated protein) and its close paralog TAZ (transcriptional coactivator with PDZ-binding motif) exert oncogenic activities in various cancers. Therefore, in this study we aimed to determine the molecular basis of curcumin-induced cell proliferation inhibition in PC cells. First, we detected the anti-tumor effects of curcumin on PC cell lines using CTG assay, Flow cytometry, clonogenic assay, wound healing assay and Transwell invasion assay. We found that curcumin significantly suppressed cell growth, weakened clonogenic potential, inhibited migration and invasion, and induced apoptosis and cell cycle arrest in PC cells. We further measured that overexpression of YAP enhanced cell proliferation and abrogated the cytotoxic effects of curcumin on PC cells. Moreover, we found that curcumin markedly down-regulated YAP and TAZ expression and subsequently suppressed Notch-1 expression. Collectively, these findings suggest that pharmacological inhibition of YAP and TAZ activity may be a promising anticancer strategy for the treatment of PC patients.

TAZ overexpression is associated with epithelial-mesenchymal transition in cisplatin-resistant gastric cancer cells

“…In summary, our study validated that CR gastric cells acquired EMT in part due to overexpression of TAZ. In addition, consistent with other study (26,48), TAZ was found to increase the expression of Notch-1 and β-catenin. Notch-1 and Wnt/β-catenin have been characterized as the drivers to induce EMT (33,49).…”

“…In line with this, we found that depletion of TAZ sensitized CR cells to cisplatin treatment. Interestingly, one natural compound, curcumin, has been reported to inhibit the expression of TAZ in bladder cancer cells (51) and pancreatic cancer cells (48). Due to non-toxic nature of natural agents, inhibition of TAZ by these compounds could be a safe and effective approach for the prevention and the treatment of gastric cancer.…”

Curcumin inhibits MCF‑7 cells by modulating the NF‑κB signaling pathway

“…Curcumin inhibits cell survival and proliferation and leads to apoptosis of lung cancer cells by reducing the expression level of Axl receptor tyrosine kinase and affecting Axl activation of non-small cell lung cancer (16). Curcumin significantly suppressed cell growth, decreased clonogenic potential, inhibited migration and invasion and induced apoptosis and cell cycle arrest in pancreatic cancer cells, liver cancer HepG2 cells and prostate cancer DU-145 cells (17,18). It has been reported that a high concentration of curcumin is able to induce apoptosis in human leukemia cells (19).…”

Curcumin inhibits superoxide dismutase-induced epithelial-to-mesenchymal transition via the PI3K/Akt/NF-κB pathway in pancreatic cancer cells

“…More importantly, curcumin is associated with minimal toxicity and it is safe at a high dose, as demonstrated by human clinical trials, in contrast with conventional cytotoxic drugs (35). Curcumin exerts its anticancer effects via multiple signaling pathways, such as Notch, mammalian target of rapamycin (mTOR), MAPK and NF-κB (5,(36)(37)(38)(39). Zhou et al (36) proved that curcumin suppressed pancreatic cancer cell growth, induced apoptosis and cell cycle arrest, weakened clonogenic potential, and inhibited migration and invasion via suppression of YAP/TAZ and Notch signaling.…”