Activation of p38/JNK pathway is responsible for embelin induced apoptosis in lung cancer cells: transitional role of reactive oxygen species.
The natural product embelin has been demonstrated to possess a wide range of therapeutic properties, however, the mechanisms by which it exerts anticancer effects are not yet clear. By monitoring the molecular changes associated during early apoptotic phase, we have identified the crucial role of oxidative stress induced MAP kinase signalling as a predominant mechanism for its anticancer effects. Treatment of A549 lung cancer cells with embelin resulted in the enhancement of phospho-p38 and phospho-JNK levels as early as 4h. Pretreatment of cells with specific inhibitors of p38 (PD169316) and JNK (SP600125) abrogated embelin-induced caspase-3 activation. Studies employing embelin in the presence or absence of specific MAP kinase inhibitors indicated that the observed changes in phosphorylation levels of p38, JNK and ERK 1/2 are solely due to embelin and not because of cross-talk between MAP kinases. Reactive oxygen species (ROS) play a crucial role in embelin induced alterations in MAP kinase phosphorylation and apoptosis as pretreatment of cells with FeTMPyP mitigated this effect. The observed changes are not due to the inhibitory effect of embelin on XIAP as cells treated with SMAC-N7-Ant peptide, a specific inhibitor of XIAP's BIR3 domain did not mimic embelin induced apoptotic effects. The findings of the present study clearly indicate the crucial role of p38 and JNK pathways in embelin induced apoptosis and provide us with new clues for improving its therapeutic efficacy.
Centre for Academy of Scientific & Innovative Research, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, Andhra Pradesh, India ; Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, Andhra Pradesh, India.
Deepa R
DR
Avisetti
Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, Andhra Pradesh, India.
K Suresh
KS
Babu
Centre for Academy of Scientific & Innovative Research, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, Andhra Pradesh, India ; Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, Andhra Pradesh, India.
Shasi V
SV
Kalivendi
D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D016650:Fluorescein-5-isothiocyanate; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D046228:Microarray Analysis; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012235:Rhodamines
D017304:Annexin A5; D000970:Antineoplastic Agents; D016227:Benzoquinones; D017382:Reactive Oxygen Species; D012235:Rhodamines; C022027:lissamine rhodamine B; D053148:Caspase 3; D053453:Caspase 9; D016650:Fluorescein-5-isothiocyanate; C010945:embelin