Apigenin Inhibits IL-6 Transcription and Suppresses Esophageal Carcinogenesis

Abstract

Esophagus cancer is the seventh cause of cancer-related deaths globally. In this study, we analyzed interleukin 6 (IL-6) gene expression in human esophagus cancer patients and showed that IL-6 mRNA levels are significantly higher in tumor tissues and negatively correlated with overall survival, suggesting that IL-6 is a potential therapeutic target for esophagus cancer. We further demonstrated that apigenin, a nature flavone product of green plants, inhibited IL-6 transcription and gene expression in human esophagus cancer Eca-109 and Kyse-30 cells. Apigenin significantly and dose-dependently inhibited cell proliferation and promoted apoptosis while stimulating the cleaved PARP (poly ADP-ribose polymerase) (C-PARP) and caspase-8 expression. It suppressed VEGF (Vascular endothelial growth Factor) expression and tumor-induced angiogenesis. Pretreatment of cells with IL-6 could completely reverse apigenin-induced cellular changes. Finally, using a preclinical nude mice model subcutaneously xenografted with Eca-109 cells, we demonstrated the in vivo antitumor activity and mechanisms of apigenin. Taken together, this study revealed for the first time that apigenin is a new IL-6 transcription inhibitor and that inhibiting IL-6 transcription is one of the mechanisms by which apigenin exhibits its anticancer effects. The potential clinical applications of apigenin in treating esophagus cancer warrant further investigations.

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“…Mechanistic studies have demonstrated that co-administration of apigenin and ABT-263 causes a decrease of AKT and ERK phosphorylation rate that reflects on FoxO3a transcription factor activity and, consequently, on the transcription of a member of Bcl-2 family protein, Noxa, that in turns activate caspase-3 [109]. Apigenin was also used in vivo in a xenograft mouse model and a reduction of tumor volume and weight was noted, confirming its potential role as a chemotherapeutic molecule [109,[113][114][115].…”

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“…Reduced cell viability and proliferation [359][360][361]. Induced cell cycle arrest at the G1 or G2/M phase [360,362,363].…”

“…Apigenin + Abivertinib had synergistic anti-cancer effects [360]. Induced apoptosis and reduced angiogenesis [361].…”

“…Apigenin also preferentially reduced viability of C6 glioma cells when co-cultured with microglia [363]. One study showed that apigenin inhibited cell proliferation, induced apoptosis, reduced vascular endothelial growth factor (VEGF) expression, and reduced tumor-induced angiogenesis in two human esophageal cancer models [361]. The inhibition of IL-6 transcription further potentiated these effects, suggesting that the inhibition of IL-6 transcription was how apigenin exhibited its anticancer effects in esophageal cancer cells.…”

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“…Jin, Shi, Liu, Chen, and Yang (2019) showed that a new type of xanthones promoted HepG2 cell apoptosis through enhancing the expression of cleaved caspase‐8, caspase‐9, and caspase‐3. Qiu et al (2019) also found that apigenin inhibited cell proliferation and induced cell apoptosis by activating the caspase‐8 expression. Besides the proapoptosis function, recent studies showed the prosurvival effects of caspase‐8.…”