title: 14-Deoxy-11,12-didehydroandrographolide induces DDIT3-dependent endoplasmic reticulum stress-mediated autophagy in T-47D breast carcinoma cells.
abstract: 14-Deoxy-11,12-didehydroandrographolide (14-DDA), a major diterpenoid isolated from Andrographis paniculata (Burm.f.) Nees, is known to be cytotoxic and elicits a non-apoptotic cell death in T-47D breast carcinoma cells. In this study, the mechanistic toxicology properties of 14-DDA in T-47D cells were further investigated. 14-DDA is found to induce the formation of endoplasmic reticulum (ER) vacuoles and autophagosomes, with concurrent upregulation of LC3-II in the breast carcinoma cells. It stimulated an increase in cytosolic calcium concentration and caused a collapse in mitochondrial membrane potential in these cells. In addition, both DDIT3 and GADD45A, molecules implicated in ER stress pathway, were significantly upregulated. DDIT3 knockdown suppressed the formation of both ER vacuoles and autophagosomes, indicating that 14-DDA-induced ER stress and autophagy is dependent on this transcription factor. Collectively, it is possible that GADD45A/p38 MAPK/DDIT3 pathway is involved in the 14-DDA-induced ER-stress-mediated autophagy in T-47D cells.
authors.affiliation: Malaysian Institute of Pharmaceuticals & Nutraceuticals, National Institutes of Biotechnology Malaysia (NIBM), Ministry of Science, Technology & Innovation, Halaman Bukit Gambir, Pulau Pinang, Malaysia; Advanced Medical & Dental Institute, Universiti Sains Malaysia, Pulau Pinang, Malaysia.
authors.forename: Heng Kean
authors.initials: HK
authors.lastname: Tan
authors.affiliation: Malaysian Institute of Pharmaceuticals & Nutraceuticals, National Institutes of Biotechnology Malaysia (NIBM), Ministry of Science, Technology & Innovation, Halaman Bukit Gambir, Pulau Pinang, Malaysia; Institute of Marine Biotechnology, Universiti Malaysia Terengganu, Kuala Terengganu, Terengganu, Malaysia.
authors.forename: Tengku Sifzizul Tengku
authors.initials: TST
authors.lastname: Muhammad
authors.affiliation: Malaysian Institute of Pharmaceuticals & Nutraceuticals, National Institutes of Biotechnology Malaysia (NIBM), Ministry of Science, Technology & Innovation, Halaman Bukit Gambir, Pulau Pinang, Malaysia; Advanced Medical & Dental Institute, Universiti Sains Malaysia, Pulau Pinang, Malaysia. Electronic address: tanml@usm.my.
authors.forename: Mei Lan
authors.initials: ML
authors.lastname: Tan
mesh_terms: D001343:Autophagy; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000096:biosynthesis*; D015854:Up-Regulation
chemical_list: C495626:14-deoxy-11,12-didehydroandrographolide; D004224:Diterpenes; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D051742:Transcription Factor CHOP; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt
keywords: 14-Deoxy-11,12-didehydroandrographolide; Autophagy; DDIT3/CHOP; Endoplasmic reticulum stress