Abstract
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.
Highlights
Obesity is one of the leading causes of chronic diseases and morbidity, including cancer, in which obesity accounts for almost 20% of all cases [1]
Since we aimed to assess the effect of vanillic acid (VA) on cancer–obesity comorbidity (COC) instead of direct effect on cancer cell death, we further investigated the effect of 1 μM of VA in 50% Conditioned Media (CM)-treated B16BL6 melanoma cells
We investigated the beneficial effect of VA in a newly established COC model of high-fat diet (HFD) and B16BL6 melanoma cell injection
Summary
Obesity is one of the leading causes of chronic diseases and morbidity, including cancer, in which obesity accounts for almost 20% of all cases [1]. The mechanistic link is yet to be clarified, the close relevance between obesity and cancer is a well-accepted theory. Various studies have discovered an epidemiological relevance between excess adiposity and malignant melanoma [2,3,4]. An experimental approach by Malvi et al showed that Orlistat, which is a widely used anti-obesity agent, reversed high-fat diet (HFD)-induced melanoma progression, suggesting the close link between obesity and melanoma malignance depends on adipokines [8]. Another possible factor is exosomes derived from adipocytes. In 2016, Lazar and colleagues suggested that exosomes derived from adipocytes induce melanoma aggressiveness by increasing fatty acid oxidation [9]
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