title: Celastrol suppresses breast cancer MCF-7 cell viability via the AMP-activated protein kinase (AMPK)-induced p53-polo like kinase 2 (PLK-2) pathway.
abstract: Celastrol, an anti-oxidant flavonoid that is widely distributed in the plant kingdom, has been suggested to have chemopreventive effects on cancer cells: however, the mechanism of this process is not completely understood. In this study, we found that celastrol suppressed the viability of breast cancer MCF-7 cells in an AMP-activated protein kinase (AMPK)-dependent fashion. Celastrol also induced an increase in reactive oxygen species (ROS) levels, leading to AMPK phosphorylation. Protein kinase C (PKC) zeta was also shown to play a role in celastrol-induced ROS generation. In addition, celastrol increased phosphorylation of the pro-apoptotic effector, p53. Inhibition of AMPK blocked celastrol-mediated p53 phosphorylation. Moreover, celastrol increased the expression of tumor suppressor polo like kinase-2 (PLK-2) in a p53-dependent manner. Neither celastrol-induced PLK-2 induction nor celastrol-mediated apoptosis inducing factor poly(ADP-ribose) polymerase-2 (PARP-2) induction was observed in p53 knock-out cells. Furthermore, add-back of PLK-2 resulted in an increase in both celastrol-mediated PARP-2 induction and celastrol-induced apoptotic index sub G1 population. Together, these results suggest that celastrol may have anti-tumor effects on MCF-7 cells via AMPK-induced p53 and PLK-2 pathways.
authors.affiliation: Department of Anatomy, Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ji Hae
authors.initials: JH
authors.lastname: Kim
authors.forename: Jung Ok
authors.initials: JO
authors.lastname: Lee
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Lee
authors.forename: Nami
authors.initials: N
authors.lastname: Kim
authors.forename: Ga Young
authors.initials: GY
authors.lastname: You
authors.forename: Ji Wook
authors.initials: JW
authors.lastname: Moon
authors.forename: Jie
authors.initials: J
authors.lastname: Sha
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Park
authors.forename: Hyeon Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D053978:Pentacyclic Triterpenes; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000099221:Protein Kinase C zeta
chemical_list: D055372:AMP-Activated Protein Kinases; D000972:Antineoplastic Agents, Phytogenic; D053978:Pentacyclic Triterpenes; D011065:Poly(ADP-ribose) Polymerases; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014315:Triterpenes; D016159:Tumor Suppressor Protein p53; D000099221:Protein Kinase C zeta; C496126:PLK2 protein, human; C050414:celastrol