Date Published: January 29, 2019
Publisher: Public Library of Science
Author(s): Alicia Bort, Belén G. Sánchez, Elena Spínola, Pedro A. Mateos-Gómez, Nieves Rodríguez-Henche, Inés Díaz-Laviada, Vladimir Trajkovic.
Capsaicin is a natural compound present in chili and red peppers and the responsible of their spicy flavor. It has recently provoked interest because of its antitumoral effects in many cell types although its action mechanism is not clearly understood. As metabolic dysregulation is one of the hallmarks of cancer cells and the key metabolic sensor in the AMP-activated kinase (AMPK), in this study we explored the ability of capsaicin to modulate AMPK activity. We found that capsaicin activated AMPK in HepG2 cells by increasing AMPK phosphorylation and its downstream target ACC. Mechanistically, we determined that capsaicin activated AMPK through the calcium/calmodulin-dependent protein kinase kinase β, CaMKKβ as either the CaMKK inhibitor STO-609 or CaMKK knock down with siRNA abrogated the activation of AMPK. Moreover, capsaicin decreased cell viability, inhibited Akt/mTOR pathway and increased reactive oxygen species (ROS) in HepG2 cells. AMPK activation was involved in the underpinning mechanism of capsaicin-induced cell death.
Natural compounds and dietary products provide an interesting area of research because of their low toxicity and potent efficacy. Capsaicin (CAP) is a natural alkaloid and the main active ingredient of spicy peppers belonging to Capsicum genus. It is used as additive in food in many cultural cuisines and it is responsible for the hot or burning sensation experienced on contact with chili peppers. Although traditionally associated with analgesic effects, it has been recently proposed that capsaicin also displays antitumor activity in various cell types and enhances the sensitivity of cancer cells to cytotoxic drugs [1–3]. In addition, laboratory data support the notion that capsaicin could act as an anti-obesity drug by increasing energy expenditure [4–6]. It has recently been shown that the intake of capsaicin reduces the insulin resistance caused by obesity in rats [7, 8]. Moreover, epidemiological data reveal that consumption of foods containing capsaicin is associated with a lower prevalence of obesity [9, 10]. Cancer cells undergo a metabolic reprogramming in order to satisfy energy demands of a continuous growth. Even in the presence of oxygen, tumors maintain anaerobic glycolysis to ensure enough levels of carbohydrate intermediates for anabolic reactions, as described by Otto Warburg nine decades ago . Furthermore, recent research indicates that metabolites themselves can be oncogenic by altering cell signaling and blocking cellular differentiation . Therefore, to impact metabolic reactions in cancer cells may be a new therapeutic strategy for this disease.
In the past decade’s phytochemicals have gain attention as chemotherapeutic agents because of their inhibition of critical tumor properties such as growth, invasion, progression and metastasis . In addition, phytochemicals have low toxicity, low cost, and public acceptance as dietary supplements. In particular capsaicin has demonstrated to exert anticancer effects in a variety of tumor types including hepatocarcinoma although the underlying mechanism remains unclear. Additionally, experimental end epidemiological data also demonstrate that capsaicin exerts anti-obesity properties and increase energy expenditure by activation of catabolic routes, thus providing a novel strategy to modulate cancer cell metabolism. Metabolic cell homeostasis is governed by the key energy sensor AMPK. In fact, targeting AMPK has become a novel strategy for cancer prevention and treatment . Thus, in this study, we investigated the mechanism underpinning AMPK activation by capsaicin and the involvement of AMPK in capsaicin-induced cell death in hepatocarcinoma cells HepG2. We found that capsaicin activates AMPK by inducing its phosphorylation by CaMKKβ. We have recently demonstrated that capsaicin sensitized HCC cells to sorafenib by activation of AMPK  which is in line with results found in this study. Recent data by Zang et al. demonstrated that the treatment of HepG2 cells with the non-pungent capsaicinoid, capsiate, increased AMPK and ACC phosphorylation and impact lipid metabolism . In bladder cancer cells capsaicin at 300 μM increase AMPK phosphorylation which authors relate with an autophagy induction by ROS, which is in good agreement with our results . Nevertheless, although our knowledge this is the first study that analyzes the mechanism involved. We have found that capsaicin-induced AMPK activation depends on TRPV1 receptor, intracellular calcium and CaMKKβ, which become potential targets to modulate AMPK activity and cell death.