Inactivation of epidermal growth factor receptor and downstream pathways in oral squamous cell carcinoma Ca9-22 cells by cardiotoxin III from Naja naja atra.
Cardiotoxin III (1), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has potential therapeutic activity in cancer. Treatment with 1 reduced phosphorylation of EGFR and Akt, as well as ERK in Ca9-22 cells. Moreover, 1-treatment inhibited constitutive activation of STAT3 and STAT5 in a time-dependent manner. Up-regulation of Bax and down-regulation of anti-apoptotic proteins including Bcl-2, Bcl-X(L), and myeloid cell leukemia-1(Mcl-1) were also found in cells treated with 1. In addition, 1-treatment disrupted mitochondrial membrane potential (DeltaPsim) and resulted in release of mitochondrial cytochrome c and activation of both caspases-9 and -3. AG1478, a specific pharmacological inhibitor of EGFR activation, mimics the cytotoxic effects of 1. Taken together, these results showed that 1 causes significant induction of apoptosis in Ca9-22 cells via abolition of the EGFR-mediated survival pathway of these cells. Thus, cardiotoxin III appears to be a potential therapeutic agent for killing oral squamous carcinoma Ca9-22 cells.
Chien
Ching-Ming
CM
Faculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan, Republic of China.
Lin
Kuei-Li
KL
Su
Jung-Chen
JC
Chang
Long-Sen
LS
Lin
Shinne-Ren
SR
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D004179:Cobra Cardiotoxin Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D004546:Elapid Venoms / Q000494:pharmacology / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011487:Protein Conformation; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects; D011799:Quinazolines; D020032:Tyrphostins / Q000494:pharmacology
D000970:Antineoplastic Agents; D004179:Cobra Cardiotoxin Proteins; D004546:Elapid Venoms; D011799:Quinazolines; D020032:Tyrphostins; C082202:cardiotoxin III, Naja naja atra; C101044:RTKI cpd; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt