Norcantharidin induces apoptosis of breast cancer cells: involvement of activities of mitogen activated protein kinases and signal transducers and activators of transcription.
Involvement of activities of mitogen-activated protein kinases (MAPKs) and signal transducers and activators of transcription (STATs) remains unsolved in norcantharidin-associated breast cancer cell apoptosis. This study investigated the anti-cancer effect of norcantharidin and its underlying mechanism in two human breast cancer cell lines, estrogen receptor (ER)- HS-578T and ER+ MCF-7 cells. Norcantharidin induced potent cytotoxicity and arrested cell growth through increasing phosphorylation of Chk1, Chk2 and total p21(Waf1/Cip1) and reducing cyclin B and cdc25c expression. It also induced apoptosis through extrinsic death receptor and intrinsic mitochondrial pathways by cytochrome c release, caspase activation, oligonucleosome appearance, PARP cleavage, and aberration of Bcl-2 family protein expression and phosphorylation. Although norcantharidin did not affect STAT1, STAT3, and STAT5 protein expression, it suppressed STAT3 and STAT5 phosphorylation in HS-578T cells, whereas it up-regulated STAT1 phosphorylation and down-regulated STAT5 phosphorylation in MCF-7 cells. Moreover, norcantharidin activated MAPK family member proteins, extracellular signal-regulated kinase (ERK), p38(MAPK) and c-Jun N-terminal kinase (JNK), were all phosphorylated by treatment. Pretreatment with selective kinase inhibitors significantly attenuated the norcantharidin-induced cytotoxicity in breast cancer cells. These findings suggest the potential involvement of MAPK and STAT pathways in norcantharidin-induced apoptogenesis. Norcantharidin may be an effective anti-cancer drug against breast cancer.
Graduate Institute of Natural Products, Kaohsiung Medical University, 100, Shih-Chuan 1st Rd., Kaohsiung 80708, Taiwan, ROC.
Pei-Yu
PY
Yang
Ming-Feng
MF
Chen
Ying-Hsien
YH
Kao
Dan-Ning
DN
Hu
Fang-Rong
FR
Chang
Yang-Chang
YC
Wu
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism*
D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D050791:STAT Transcription Factors; C069741:norcantharidin; D045304:Cytochromes c; D020928:Mitogen-Activated Protein Kinases