title: Cryptotanshinone activates p38/JNK and inhibits Erk1/2 leading to caspase-independent cell death in tumor cells.
abstract: Cryptotanshinone (CPT), a natural compound isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, the underlying mechanism is not well understood. Here, we show that CPT induced caspase-independent cell death in human tumor cells (Rh30, DU145, and MCF-7). Besides downregulating antiapoptotic protein expression of survivin and Mcl-1, CPT increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK), and inhibited phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2). Inhibition of p38 with SB202190 or JNK with SP600125 attenuated CPT-induced cell death. Similarly, silencing p38 or c-Jun also in part prevented CPT-induced cell death. In contrast, expression of constitutively active mitogen-activated protein kinase kinase 1 (MKK1) conferred resistance to CPT inhibition of Erk1/2 phosphorylation and induction of cell death. Furthermore, we found that all of these were attributed to CPT induction of reactive oxygen species (ROS). This is evidenced by the findings that CPT induced ROS in a concentration- and time-dependent manner; CPT induction of ROS was inhibited by N-acetyl-L-cysteine (NAC), a ROS scavenger; and NAC attenuated CPT activation of p38/JNK, inhibition of Erk1/2, and induction of cell death. The results suggested that CPT induction of ROS activates p38/JNK and inhibits Erk1/2, leading to caspase-independent cell death in tumor cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, 71130, USA.
authors.forename: Wenxing
authors.initials: W
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Odaka
authors.forename: Sanket
authors.initials: S
authors.lastname: Awate
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhou
authors.forename: Tao
authors.initials: T
authors.lastname: Shen
authors.forename: Shizhong
authors.initials: S
authors.lastname: Zheng
authors.forename: Yin
authors.initials: Y
authors.lastname: Lu
authors.forename: Shile
authors.initials: S
authors.lastname: Huang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D020169:Caspases / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010616:Phenanthrenes / Q000494:pharmacology* / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004365:Drugs, Chinese Herbal; D010616:Phenanthrenes; C037886:cryptotanshinone; D048031:JNK Mitogen-Activated Protein Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases