Taiwan cobra cardiotoxin III inhibits Src kinase leading to apoptosis and cell cycle arrest of oral squamous cell carcinoma Ca9-22 cells.
Cardiotoxin III (CTX III), a basic polypeptide with 60-amino acid residues isolated from Naja naja atra venom, has been reported to have cytotoxic activity. CTX III exerted cytotoxicity with the S-phase cell cycle arrest, correlated with a marked decrease in the expression levels of cyclin A, cyclin B, and cyclin-dependent kinase 1 (CDK1), and apoptosis, accompanied with Bax and Bad up-regulation, and the down-regulation of Bcl-2, p-Bad, and X-linked inhibitor of apoptosis (XIAP) with cytochrome c release and sequential activation of caspase-9 and caspase-3 in Ca9-22 cells. Mechanistic studies showed that CTX III suppressed the phosphorylation of Src, EGFR, STAT3, STAT5, Akt, and activation of PI3 K (p110). Moreover, Src inactivation was observed earlier than that of the EGFR and the Src inhibitor PP2 suppressed the levels of phospho-EGFR, phospho-STAT3, phospho-STAT5, phospho-Akt, and PI3 K(p110). The PP2 also caused the S-phase arrest and apoptosis, and led to down-regulation of Bcl-2, p-Bad, XIAP, cyclin A, cyclin B, and CDK1, and up-regulation of Bax and Bad, similar to that observed in CTX III treatment. Taken together, these results indicate that CTX III induces apoptosis and S-phase arrest in Ca9-22 cells via concomitant inactivation of the Src, EGFR, STAT3, STAT5, PI3 K(p110), and Akt signaling pathways.
Chien
Ching-Ming
CM
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC.
Chang
Shang-Yu
SY
Lin
Kuei-Li
KL
Chiu
Chien-Chih
CC
Chang
Long-Sen
LS
Lin
Shinne-Ren
SR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D004179:Cobra Cardiotoxin Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004546:Elapid Venoms / Q000737:chemistry; D017815:Elapidae; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009062:Mouth Neoplasms; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
D004179:Cobra Cardiotoxin Proteins; D004546:Elapid Venoms; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051025:bcl-Associated Death Protein; C082202:cardiotoxin III, Naja naja atra; C512478:EGFR protein, human; D066246:ErbB Receptors; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt