Obesity is known to be associated with risk and aggressiveness of cancer. Melanoma, the most lethal type of skin cancer, is also closely related to the prevalence of obesity. In this study, we established a cancer–obesity comorbidity (COC) model to investigate the effects of vanillic acid (VA). After a five-week administration with a high-fat diet (HFD) to induce obesity, subcutaneous allograft of B16BL6 cells were followed, and VA was orally administrated for an additional two weeks. VA-fed mice showed significantly decreased body weight and white adipose tissue (WAT) weight, which were due to increased thermogenesis and AMPK activation in WATs. Growth of cancer was also suppressed. Mechanistic studies revealed increased apoptosis and autophagy markers by VA; however, caspase 3 was not involved. Since signal transducer and activator of transcription 3 (STAT3) is suggested as an important pathway linking obesity and cancer, we further investigated to find out if STAT3 phosphorylation was repressed by VA treatment, and this was again confirmed in a COC cell model of adipocyte conditioned medium-treated B16BL6 melanoma cells. Overall, our results show VA induces STAT3-mediated autophagy to inhibit cancer growth and thermogenesis to ameliorate obesity in COC. Based on these findings, we suggest VA as a candidate therapeutic agent for COC treatment.

Although our previous study revealed that gamma-irradiated chrysin enhanced anti-inflammatory activity compared to intact chrysin, it remains unclear whether the chrysin derivative, CM1, produced by gamma irradiation, negatively regulates toll-like receptor (TLR) signaling. In this study, we investigated the molecular basis for the downregulation of TLR4 signal transduction by CM1 in macrophages. We initially determined the appropriate concentration of CM1 and found no cellular toxicity below 2 μg/mL. Upon stimulation with lipopolysaccharide (LPS), CM1 modulated LPS-stimulated inflammatory action by suppressing the release of proinflammatory mediators (cytokines TNF-α and IL-6) and nitric oxide (NO) and downregulated the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways. Furthermore, CM1 markedly elevated the expression of the TLR negative regulator toll-interacting protein (Tollip) in dose- and time-dependent manners. LPS-induced expression of cell surface molecules (CD80, CD86, and MHC class I/II), proinflammatory cytokines (TNF-α and IL-6), COX-2, and iNOS-mediated NO were inhibited by CM1; these effects were prevented by the knockdown of Tollip expression. Additionally, CM1 did not affect the downregulation of LPS-induced expression of MAPKs and NF-κB signaling in Tollip-downregulated cells. These findings provide insight into effective therapeutic intervention of inflammatory disease by increasing the understanding of the negative regulation of TLR signaling induced by CM1.