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Capsaicin induces cytotoxicity in human osteosarcoma MG63 cells through TRPV1-dependent and -independent pathways.

ABSTRACT: An accumulating body of evidence has shown that capsaicin induces apoptosis in various tumor cells as a mechanism of its anti-tumor activity. However, the effects of capsaicin on osteosarcoma have not been studied extensively. In the current study, we explore the molecular mechanism of capsaicin-mediated tumor suppressive function in osteosarcoma. We found that capsaicin-induced apoptosis and the activation of transient receptor potential receptor vanilloid 1 (TRPV1) in a dose- and time-dependent manner in human osteosarcoma MG63 cells in vitro. Blocking TRPV1 using capsazepine attenuated the capsaicin-induced cytotoxicity, mitochondrial dysfunction, overproduction of reactive oxygen species (ROS) and decrease in superoxide dismutase (SOD) activity. In addition, the results demonstrated that capsaicin induced the activation of adenosine 5'-monophosphate-activated protein kinase (AMPK), p53 and C-jun N-terminal kinase (JNK). In addition, Compound C (antagonist of AMPK) attenuated the activation of p53, which appeared to be TRPV1 independent. Taken together, the present study suggests that capsaicin effectively causes cell death in human osteosarcoma MG63 cells via the activation of TRPV1-dependent (mitochondrial dysfunction, and overproduction of ROS and JNK) and TRPV1-independent (AMPK-p53) pathways. Thus, capsaicin may be a potential anti-osteosarcoma agent.

SUBMITTER: Bao Z

PROVIDER: S-EPMC6592244 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Capsaicin induces cytotoxicity in human osteosarcoma MG63 cells through TRPV1-dependent and -independent pathways.

Bao Zhengqi Z Dai Xiusong X Wang Peter P Tao Yisheng Y Chai Damin D

Cell cycle (Georgetown, Tex.) 20190529 12

An accumulating body of evidence has shown that capsaicin induces apoptosis in various tumor cells as a mechanism of its anti-tumor activity. However, the effects of capsaicin on osteosarcoma have not been studied extensively. In the current study, we explore the molecular mechanism of capsaicin-mediated tumor suppressive function in osteosarcoma. We found that capsaicin-induced apoptosis and the activation of transient receptor potential receptor vanilloid 1 (TRPV1) in a dose- and time-dependen ...[more]

PMID: 31095448

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Project description:TRPV1 ion channels mediate the response to painful heat, extracellular acidosis, and capsaicin, the pungent extract from plants in the Capsicum family (hot chili peppers) (Szallasi, A., and P.M. Blumberg. 1999. Pharmacol. Rev. 51:159-212; Caterina, M.J., and D. Julius. 2001. Annu. Rev. Neurosci. 24:487-517). The convergence of these stimuli on TRPV1 channels expressed in peripheral sensory nerves underlies the common perceptual experience of pain due to hot temperatures, tissue damage and exposure to capsaicin. TRPV1 channels are nonselective cation channels (Caterina, M.J., M.A. Schumacher, M. Tominaga, T.A. Rosen, J.D. Levine, and D. Julius. 1997. Nature. 389:816-824). When activated, they produce depolarization through the influx of Na+, but their high Ca2+ permeability is also important for mediating the response to pain. In particular, Ca2+ influx is thought to be required for the desensitization to painful sensations over time (Cholewinski, A., G.M. Burgess, and S. Bevan. 1993. Neuroscience. 55:1015-1023; Koplas, P.A., R.L. Rosenberg, and G.S. Oxford. 1997. J. Neurosci. 17:3525-3537). Here we show that in inside-out excised patches from TRPV1 expressed in Xenopus oocytes and HEK 293 cells, Ca2+/calmodulin decreased the capsaicin-activated current. This inhibition was not mimicked by Mg2+, reflected a decrease in open probability, and was slowly reversible. Furthermore, increasing the calmodulin concentration in our patches by coexpression of wild-type calmodulin with TRPV1 produced inhibition by Ca2+ alone. In contrast, patches excised from cells coexpressing TRPV1 with a mutant calmodulin did not respond to Ca2+. Using an in vitro calmodulin-binding assay, we found that TRPV1 in oocyte lysates bound calmodulin, although in a Ca2+-independent manner. Experiments with GST-fusion proteins corresponding to regions of the channel NH2-terminal domain demonstrated that a stretch of approximately 30 amino acids adjacent to the first ankyrin repeat bound calmodulin in a Ca2+-dependent manner. The physiological response to pain involves an influx of Ca2+ through TRPV1. Our results indicate that this Ca2+ influx may feed back on the channels, inhibiting their gating. This type of feedback inhibition could play a role in the desensitization produced by capsaicin.

Dataset Information

Capsaicin induces cytotoxicity in human osteosarcoma MG63 cells through TRPV1-dependent and -independent pathways.

Publications

Capsaicin induces cytotoxicity in human osteosarcoma MG63 cells through TRPV1-dependent and -independent pathways.

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