Atorvastatin potentiates the chemosensitivity of human liver cancer cells to cisplatin via downregulating YAP1

Abstract

Atorvastatin is a competitive inhibitor of β-hydroxy β-methylglutaryl-CoA reductase, which is involved in anticancer effects in numerous types of cancer, including in human liver cancer. However, its functions and underlying mechanisms of chemosensitivity in liver cancer remain to be elucidated. The present study investigated the effect of atorvastatin on cisplatin chemosensitivity and its molecular mechanisms, with a focus on the Yes1-associated transcriptional regulator (YAP1) protein. The present study demonstrated that atorvastatin significantly potentiated chemosensitivity to cisplatin in the liver cancer HepG2 and Huh-7 cell lines. Furthermore, cell survival and apoptosis in liver cancer cell lines were analyzed using MTT assay and flow cytometry, respectively. Atorvastatin suppressed HepG2 and Huh-7 cell viability in a dose-dependent manner, similar to cisplatin and paclitaxel. Subtoxic levels of atorvastatin significantly increased cisplatin-induced apoptosis in Huh-7 cells. Atorvastatin-promoted chemosensitivity was predominantly mediated by caspase 3, caspase 9 and poly-(ADP ribose)-polymerase activation, and YAP1 downregulation. Finally, YAP1 overexpression significantly reversed the susceptibility of Huh-7 cells to cisplatin. Overall, the results of the present study suggested the underlying mechanisms of atorvastatin chemosensitivity in inducing liver cancer cell apoptosis via downregulating YAP1 and implicated the potential application of atorvastatin-potentiated chemosensitivity in liver cancer therapy.

Atorvastatin improves cisplatin sensitivity through modulation of cholesteryl ester homeostasis in breast cancer cells

“…Fromigué et al [27] suggested that high doses of ATV increased drug sensitivity through the modulation of matrix metalloprotease 2 in osteosarcoma cells. On the other hand, Guo and collaborators [28] showed that liver cancer cells (Huh-7) became more sensitive to CDDP in the presence of 100 µM ATV. Here, we report a correlation between the modulation of ACAT-1 expression upon exposure to CDDP in combination with ATV in MDA-MB-231 cells.…”

“…Many statins have shown the potential to improve therapeutic outcomes of chemotherapy regimens in bladder cancer [26], osteosarcoma [27], liver [28], and pancreatic cancer [29]. As such, we evaluated the effect of ATV on CDDP sensitivity in BC cells.…”

Enhancement of the anticancer effect of atorvastatin-loaded nanoemulsions by improving oral absorption via multivalent intestinal transporter-targeting lipids

“…Finally, it can induce autophagy in hepatocellular carcinoma and colorectal carcinoma cells by activating protein kinase (AMPK)/p21 signaling and stimulating the endoplasmic reticulum (ER) stress response (Ma et al., 2019 ). Moreover, ATV shows synergistic antiproliferative, antiangiogenic, and apoptotic actions against various types of cancers (e.g., colon, lung, and prostate), in combination with anticancer agents such as doxorubicin, cisplatin, paclitaxel, topotecan, bevacizumab, and celecoxib (Zheng et al., 2010 ; Buranrat et al., 2017 ; Tan et al., 2017 ; Ma et al., 2019 ; Guo et al., 2020 ; Lee et al., 2021 ; Marti et al., 2021 ). Therefore, ATV has received considerable interest as a potential therapeutic agent for use in cancer treatment.…”

Atorvastatin regulates the migration and invasion of prostate cancer through the epithelial-mesenchymal transformation and matrix metalloproteinase pathways

“…It is mainly used clinically to reduce cholesterol in the blood and the risk for cardiovascular and cerebrovascular diseases. Current studies have found that ATO has anti-tumor effects in cervical cancer, liver cancer, cholangiocarcinoma, and PCa [ 5 6 7 8 9 10 ]. Statins, especially ATO, can improve the survival of patients with PCa and are expected to become complementary treatment options for PCa, but the specific mechanism of their drug effect is unclear [ 11 ].…”