Quercetin acts as a novel anti-cancer drug to suppress cancer aggressiveness and cisplatin-resistance in nasopharyngeal carcinoma (NPC) through regulating the yes-associated protein/Hippo signaling pathway

Background: Quercetin has been proven to be effective for Cancer treatment, including nasopharyngeal carcinoma (NPC). Also, Quercetin sensitizes Cancer cells to current chemical drugs to improve their therapeutic efficacy. However, up until now, the molecular mechanisms that quercetin exerted its therapeutic effects on NPC have not been fully delineated.

Methods: Cell proliferation abilities were examined by CCK-8 assay and colony formation assay. Real-Time qPCR and Western Blot analysis were used to detect gene expressions at RNA and protein levels. Cell mobility was determined by wound scratch assay and transwell assay. Cell death was detected using flow cytometry (FCM). Tumorigenesis of the NPC cells was determined by in vivo tumor-bearing mice models. Hematoxylin and eosin (H&E) and TUNEL staining were used to detect the tumor metastasis to lung tissues and dead cells, respectively.

Results: Here, we validated that quercetin exerted its anti-tumor effects and increased cisplatin-sensitivity in NPC in vitro and in vivo. Specifically, quercetin inhibited NPC cell proliferation, viability, mobility, epithelial-mesenchymal transition (EMT), and tumorigenesis, and induced cell death, resulting in the inhibition of NPC progression. In addition, the NPC cells were subjected to a continuously increasing doses of cisplatin to generate cisplatin-resistant NPC (NPC/CDDP) cells. Interestingly, quercetin significantly enhanced the cytotoxic effects of high-dose cisplatin on NPC/CDDP cells. Furthermore, the potential underlying mechanisms were uncovered, and the results evidenced that quercetin inhibited Yes-associated protein (YAP) expression and its translocation to the nucleus, leading to the recovery of the Hippo pathway, inhibition of Cancer progression, and increase in cisplatin-resistance. Mechanistically, upregulation of YAP by its gene manipulating vectors abrogated the inhibiting effects of quercetin on NPC malignant phenotypes, which also made NCP/CDDP cells irresponsive to high-dose cisplatin-quercetin co-treatments.

Conclusion: Collectively, our data evidenced that quercetin inhibited YAP to recover the Hippo pathway, which further inhibited NPC pathogenesis and increased susceptibility of NCP/CDDP cells to cisplatin treatment.

Cancer biology; Drug resistance; Hippo pathway; Nasopharyngeal carcinoma; Yes-associated protein.