Khz (fusion of Ganoderma lucidum and Polyporus umbellatus mycelia) induces apoptosis by increasing intracellular calcium levels and activating JNK and NADPH oxidase-dependent generation of reactive oxygen species.
Khz is a compound derived from the fusion of Ganoderma lucidum and Polyporus umbellatus mycelia that inhibits the growth of cancer cells. The results of the present study show that Khz induced apoptosis preferentially in transformed cells and had only minimal effects on non-transformed cells. Furthermore, Khz induced apoptosis by increasing the intracellular Ca(2+) concentration ([Ca(2+)](i)) and activating JNK to generate reactive oxygen species (ROS) via NADPH oxidase and the mitochondria. Khz-induced apoptosis was caspase-dependent and occurred via a mitochondrial pathway. ROS generation by NADPH oxidase was critical for Khz-induced apoptosis, and although mitochondrial ROS production was also required, it appeared to occur secondary to ROS generation by NADPH oxidase. Activation of NADPH oxidase was demonstrated by the translocation of regulatory subunits p47(phox) and p67(phox) to the cell membrane and was necessary for ROS generation by Khz. Khz triggered a rapid and sustained increase in [Ca(2+)](i), which activated JNK. JNK plays a key role in the activation of NADPH oxidase because inhibition of its expression or activity abrogated membrane translocation of the p47(phox) and p67(phox) subunits and ROS generation. In summary, these data indicate that Khz preferentially induces apoptosis in cancer cells, and the signaling mechanisms involve an increase in [Ca(2+)](i), JNK activation, and ROS generation via NADPH oxidase and mitochondria.
Department of Radiotherapy, The First Affiliated Hospital, Guangxi Medical University, Nanning, China.
Tae Hwan
TH
Kim
Ju sung
Js
Kim
Zoo haye
Zh
Kim
Ren Bin
RB
Huang
Ren Sheng
RS
Wang
D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D025282:Mycelium / Q000737:chemistry; D019255:NADPH Oxidases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D055492:Polyporus / Q000737:chemistry; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020940:Reishi / Q000737:chemistry; D014020:Tissue Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
D001688:Biological Products; C579322:Khz extract; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D014020:Tissue Extracts; C079789:neutrophil cytosol factor 67K; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D048055:Mitogen-Activated Protein Kinase 8; D002118:Calcium