title: Capsaicin induces apoptosis in human osteosarcoma cells through AMPK-dependent and AMPK-independent signaling pathways.
abstract: Recent studies have focused on the anti-tumor activity of capsaicin. However, the potential effects of capsaicin in osteosarcoma cells and the underlying mechanisms are not fully understood. In the current study, we observed that capsaicin-induced growth inhibition and apoptosis in cultured osteosarcoma cells (U2OS and MG63), which were associated with a significant AMP-activated protein kinase (AMPK) activation. AMPK inhibition by compound C or RNA interference suppressed capsaicin-induced cytotoxicity, while AMPK activators (AICAR and A769662) promoted osteosarcoma cell death. For the mechanism study, we found that AMPK activation was required for capsaicin-induced mTORC1 (mTOR complex 1) inhibition, B cell lymphoma 2 (Bcl-2) downregulation and Bax upregulation in MG63 cells. Capsaicin administration induced p53 activation, mitochondrial translocation and Bcl-2 killer association, such effects were dependent on AMPK activation. Interestingly, we observed a significant pro-apoptotic c-Jun NH2-terminal kinases activation by capsaicin in MG63 cells, which appeared to be AMPK independent. In conclusion, capsaicin possessed strong efficacy against human osteosarcoma cells. Molecular studies revealed that capsaicin activated AMPK-dependent and AMPK-independent signalings to mediate cell apoptosis. The results of this study should have significant translational relevance in managing this deadly malignancy.
authors.affiliation: Department of Orthopedics, Gongli Hospital of Pudong New District, No. 219, Miaopu Road, Pudong New District, Shanghai, 200135, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ying
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tie-Yi
authors.initials: TY
authors.lastname: Yang
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Ding
authors.forename: Shu-Yi
authors.initials: SY
authors.lastname: Liu
authors.forename: Jin
authors.initials: J
authors.lastname: Shao
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.forename: Xin-Bing
authors.initials: XB
authors.lastname: Fan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000982:Antipruritics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
chemical_list: D000982:Antipruritics; D007004:Hypoglycemic Agents; D046912:Multiprotein Complexes; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D012265:Ribonucleotides; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D000620:Aminoimidazole Carboxamide; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D053148:Caspase 3; C031143:AICA ribonucleotide; D002211:Capsaicin