Reversion of trichostatin A resistance via inhibition of the Wnt signaling pathway in human pancreatic cancer cells

Abstract

Drug resistance is a major impediment to successful chemotherapy in pancreatic cancer (PC) patients. We investigated the effect of Wnt/β-catenin signaling inhibition by wnt-c59 on chemoresistance in a trichostatin A-resistant Panc-1 cell line (Panc-1/TSA). Panc-1/TSA cells were treated with the Wnt/β‑catenin signaling inhibitor wnt-c59 (10 µmol · l-1) and/or trichostatin A (TSA; 10 µmol · l-1) for 24 h. CCK-8 assay was utilized to analyze the interactive effect of TSA and wnt-c59 on induction of apoptosis of the Panc-1/TSA cells. Cell apoptosis was measured by flow cytometry. Real-time PCR and western blotting were used to assess Wnt/β-catenin signaling, epithelial-mesenchymal transition (EMT) and multidrug resistance (MDR). Real-time cell analysis (RTCA) was used to detect the cell migration ability. After wnt-c59 treatment for 24 h, relative genes and transcriptional targets of Wnt/β-catenin signaling were downregulated (P<0.05). CCK-8 assay indicated that the combination of TSA and wnt-c59 had a synergistic effect on induction of Panc-1/TSA cell apoptosis. As detected by FACS, cell apoptosis rates increased significantly (P<0.05). The results of RTCA showed that the cell indices of the control group, wnt-c59 group, TSA group and TSA+wnt-c59 combination group were 1.2842±0.0257, 1.2155±0.0282, 1.2533±0.0194 and 0.8541±0.0250, respectively. In accordance, MMP-9 protein in the wnt-c59 treatment groups was decreased compared to the non-wnt-c59 treatment groups. Meanwhile, E-cadherin protein was upregulated and vimentin protein was downregulated, both of which are characteristic markers of EMT. Chemoresistant gene MDR1 and P-glycoprotein (P-gp) in the wnt-c59 treatment groups had a reduced expression compared to the non-wnt-c59 treatment groups. This study revealed that TSA sensitivity, migration ability, and the EMT phenotype in Panc-1/TSA cells were reversed following Wnt/β-catenin signaling inhibition.

Tankyrase 1 inhibitior XAV939 increases chemosensitivity in colon cancer cell lines via inhibition of the Wnt signaling pathway

“…Intensive study of the Wnt signaling pathway shows accumulating evidence suggesting that activation of WNT signaling pathway in CSCs contribute to their chemoresistance. Therefore, targeting WNT signaling pathway to reverse CSC multidrug resistance in CRC cells is a promising way for improving chemotherapeutic effects ( 19 – 22 ).…”

Tyrphostin B42 attenuates trichostatin A-mediated resistance in pancreatic cancer cells by antagonizing IL-6/JAK2/STAT3 signaling

“…It has been reported that PCCs were resistant to HDAC inhibitor trichostatin A (TSA) (8). Aberrant activation of Wnt/β-catenin signaling contributes to TSA resistance through epithelial-mesenchymal transition.…”

“…HDAC inhibitors, which interfere with the function of histone deacetylase (HDAC), are emerging as potent anticancer agents as a result of their effective anti-proliferative activity in a wide variety of tumors, mediated by mitotic defects through the aberrant acetylation of histone Tyrphostin B42 attenuates trichostatin A-mediated resistance in pancreatic cancer cells by antagonizing IL-6/JAK2/STAT3 signaling and non-histone proteins (3,7). However, our previous study revealed that pancreatic cancer cells (PCCs) were resistant to HDAC inhibitor trichostatin A (TSA) (8). Over-proliferative activity and inhibition of apoptosis indicated that some proliferation-related signaling pathways may be involved in the process of TSA-mediated resistance in PCCs (8,9).…”

“…However, our previous study revealed that pancreatic cancer cells (PCCs) were resistant to HDAC inhibitor trichostatin A (TSA) (8). Over-proliferative activity and inhibition of apoptosis indicated that some proliferation-related signaling pathways may be involved in the process of TSA-mediated resistance in PCCs (8,9). According to previous studies, IL-6 is a well-studied proinflammatory cytokine with numerous links to a variety of malignancies (10).…”

Recent advances in pancreatic cancer: biology, treatment, and prevention

“…It has been also found that β-catenin accumulation and signaling could be increased through paracrine signaling taking place in the PDAC micro-environment [61]. In a recent investigation, it has been found that Wnt/β-catenin signaling inhibition by wnt-c59 results in reversal of TSA sensitivity, migration ability, and the EMT phenotype in trichostatin A-resistant Panc-1 cells (Panc-1/TSA) [67].…”