Wogonin induces cross-regulation between autophagy and apoptosis via a variety of Akt pathway in human nasopharyngeal carcinoma cells.
Autophagy as well as apoptosis is an emerging target for cancer therapy. Wogonin, a flavonoid compound derived from the traditional Chinese medicine of Huang-Qin, has anticancer activity in many cancer cells including human nasopharyngeal carcinoma (NPC). However, the involvement of autophagy in the wogonin-induced apoptosis of NPC cells was still uninvestigated. In this study, we found wogonin-induced autophagy had interference on the process of apoptosis. Wogonin-induced autophagy formation evidenced by LC3 I/II cleavage, acridine orange (AO)-stained vacuoles and the autophagosome/autolysosome images of TEM analysis. Activation of autophagy with rapamycin resulted in increased wogonin-mediated autophagy via inhibition of mTOR/P70S6K pathway. The functional relevance of autophagy in the antitumor activity was investigated by annexin V-positive stained cells and PARP cleavage. Induction of autophagy by rapamycin ameliorated the wogonin-mediated apoptosis, whereas inhibition of autophagy by 3-methyladenine (3-MA) or bafilomycin A1 increased the apoptotic effect. Interestingly, this study also found, in addition the mTOR/P70S6K pathway, wogonin also inhibited Raf/ERK pathway, a variety of Akt pathways. Inactivation of PI(3) K/Akt by their inhibitors significantly induced apoptosis and markedly sensitized the NPC cells to wogonin-induced apoptosis. This anticancer effect of Akt was further confirmed by SH6, a specific inhibitor of Akt. Importantly, inactivation of its downstream molecule ERK by PD98059, a MEK inhibitor, also induced apoptosis. This study indicated wogonin-induced both autophagy and apoptosis through a variety of Akt pathways and suggested modulation of autophagy might provide profoundly the potential therapeutic effect.
Center for General Studies, Chang Gung University, Taoyuan, Taiwan. chowse@mail.cgu.edu.tw
Shu-Er
SE
Chow
Yu-Wen
YW
Chen
Chi-Ang
CA
Liang
Yao-Kuan
YK
Huang
Jong-Shyan
JS
Wang
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D002277:Carcinoma; D045744:Cell Line, Tumor; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D044950:Flavanones / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism
D000225:Adenine; D004365:Drugs, Chinese Herbal; D048049:Extracellular Signal-Regulated MAP Kinases; D044950:Flavanones; D005419:Flavonoids; D018942:Macrolides; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D048490:raf Kinases; C025946:3-methyladenine; C040929:bafilomycin A1; C546842:MTOR protein, human; C085514:wogonin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one