title: Cinnamtannin D1 from Rhododendron formosanum Induces Autophagy via the Inhibition of Akt/mTOR and Activation of ERK1/2 in Non-Small-Cell Lung Carcinoma Cells.
abstract: In our previous study, ursolic acid present in the leaves of Rhododendron formosanum was found to possess antineoplastic activity. We further isolated and unveiled a natural product, cinnamtannin D1 (CNT D1), an A-type procyanidin trimer in R. formosanum also exhibiting anticancer efficacy that induced G1 arrest (83.26 ± 3.11% for 175 μM CNT D1 vs 69.28 ± 1.15% for control, p < 0.01) and autophagy in non-small-cell lung carcinoma (NSCLC) cells. We found that CNT D1-mediated autophagy was via the noncanonical pathway, being beclin-1-independent but Atg5 (autophagy-related genes 5)-dependent. Inhibition of autophagy with a specific inhibitor enhanced cell death, suggesting a cytoprotective function for autophagy in CNT D1-treated NSCLC cells. Moreover, CNT D1 inhibited the Akt/mammalian target of the rapamycin (mTOR) pathway and activated the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway, resulting in induction of autophagy.
authors.affiliation: Department of Health and Nutrition Biotechnology, College of Health Science, Asia University , Taichung 41354, Taiwan.
authors.forename: Tzong-Der
authors.initials: TD
authors.lastname: Way
authors.forename: Shang-Jie
authors.initials: SJ
authors.lastname: Tsai
authors.forename: Chao-Min
authors.initials: CM
authors.lastname: Wang
authors.forename: Yun-Lian
authors.initials: YL
authors.lastname: Jhan
authors.affiliation: Department of Food Science, Rutgers University , New Brunswick, New Jersey United States.
authors.forename: Chi-Tang
authors.initials: CT
authors.lastname: Ho
authors.affiliation: Department of Life Sciences, National Cheng Kung University , Tainan 701, Taiwan.
authors.forename: Chang-Hung
authors.initials: CH
authors.lastname: Chou
mesh_terms: D000872:Anthocyanins / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D010936:Plant Extracts / Q000008:administration & dosage*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D029793:Rhododendron / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000872:Anthocyanins; D000970:Antineoplastic Agents; D010936:Plant Extracts; C425558:cinnamtannin A2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Akt/mTOR; ERK1/2; Rhododendron formosanum; cinnamtannin D1; non-small-cell lung carcinoma