Atorvastatin Augments Gemcitabine-Mediated Anti-Cancer Effects by Inhibiting Yes-Associated Protein in Human Cholangiocarcinoma Cells

Abstract

Cholangiocarcinoma (CCA) is associated with high mortality rates because of its resistance to conventional gemcitabine-based chemotherapy. Hydroxy-methyl-glutaryl-coenzyme A reductase inhibitors (statins) reportedly exert anti-cancer effects in CCA and lower the risk of CCA; however, the underlying mechanism of these effects remains unclear. The proliferative and oncogenic activities of the transcriptional co-activator Yes-associated protein (YAP) are driven by its association with the TEA domain (TEAD) of transcription factors; thereby, upregulating genes that promote cell growth, inhibit apoptosis, and confer chemoresistance. This study investigated the effects of atorvastatin in combination with gemcitabine on the progression of human CCA associated with YAP oncogenic regulation. Both atorvastatin and gemcitabine concentration-dependently suppressed the proliferation of HuCCT-1 and KKU-M213 human CCA cells. Moreover, both agents induced cellular apoptosis by upregulating the pro-apoptotic marker BAX and downregulating the anti-apoptotic markers MCL1 and BCL2. Atorvastatin also significantly decreased the mRNA expression of the TEAD target genes CTGF, CYR61, ANKRD1, and MFAP5 in both CCA cell lines. A xenograft tumor growth assay indicated that atorvastatin and gemcitabine potently repressed human CCA cell-derived subcutaneous tumor growth by inhibiting YAP nuclear translocation and TEAD transcriptional activation. Notably, the anti-cancer effects of the individual agents were significantly enhanced in combination. These results indicate that gemcitabine plus atorvastatin could serve as a potential novel treatment option for CCA.

Atractylodin and β-eudesmol from Atractylodes lancea (Thunb.) DC. Inhibit Cholangiocarcinoma Cell Proliferation by Downregulating the Notch Signaling Pathway

“…YAP is one of the upstream molecules of the Notch signaling pathway. It was reported to play a role in the mediation of resistance of cancer cells to gemcitabine (Gujral and Kirschner, 2017;Nguyen and Yi, 2019), and gemcitabine in combination with a YAP inhibitor was shown to enhance the efficacy of gemcitabine in CCA (Kitagawa et al, 2020) Other upstream signaling molecules of the Notch signaling pathway, i.e., JAG1, mTOR and PI3K were also downregulated after exposing HuCCT-1 cells to both compounds, but with relatively lower activity compared with Notch1 receptor and YAP. JAG1 (Jagged1) is a ligand for the Notch receptor; it has an important function in both physiological and pathological conditions, including cancer (angiogenesis, cell proliferation, cancer stem cells, invasion, and metastasis) (Li et al, 2014;Xiu et al, 2020).…”

Statin as a Potential Chemotherapeutic Agent: Current Updates as a Monotherapy, Combination Therapy, and Treatment for Anti-Cancer Drug Resistance

“…However, treatment with gemcitabine in combination with statins, such as simvastatin, atorvastatin, rosuvastatin, fluvastatin, pitavastatin, and pravastatin is an effective treatment for pancreatic cancers, particularly gemcitabine-resistant cancer [ 141 ]. Furthermore, it synergistically improved the anti-cancer efficacy of gemcitabine in human cholangiocarcinoma cells [ 142 ]. The synergistic anti-cancer effect of gemcitabine and pitavastatin on pancreatic ductal adenocarcinoma (PDAC) is mediated by cell-cycle arrest at sub-G1 and S phases, leading to downregulation of cyclin A2/CDK2 and upregulation of p21/p27.…”

Noncoding RNAs Associated with Therapeutic Resistance in Pancreatic Cancer

“…The blocking of YAP/TAZ signaling is expected to reduce the development of therapeutic resistance [ 167 , 168 ]. Gemcitabine efficacy can be augmented by atorvastatin, which suppresses YAP/TAZ signaling [ 169 ] (also see Section 2.3.4 describing the Hippo pathway and YAP1). In PaC, the downregulation of miR-455-3p and miR-1285 aggravates gemcitabine resistance.…”