title: Manumycin A induces apoptosis in malignant pleural mesothelioma through regulation of Sp1 and activation of the mitochondria-related apoptotic pathway.
abstract: Manumycin A (Manu A) is a natural product isolated from Streptomyces parvulus and has been reported to have anti-carcinogenic and anti-biotic properties. However, neither its molecular mechanism nor its molecular targets are well understood. Thus, the aim of the present study was to explore the possibility that Manu A has cancer preventive and chemotherapeutic effects on malignant pleural mesothelioma (MPM) through regulation of Sp1 and induction of mitochondrial cell death pathway. Manu A inhibited the cell viability of MSTO-211H and H28 cells in a concentration‑dependent manner as determined by MTS assay. IC50 values were calculated as 8.3 and 4.3 µM in the MSTO-311H and H28 cells following 48 h incubation, respectively. Manu A induced a significant increase in apoptotic indices as shown by DAPI staining, Annexin V assay, multi-caspase activity and mitochondrial membrane potential assay. The downregulation of Sp1 mRNA and protein expression by Manu A led to apoptosis by suppressing Sp1-regulated proteins (cyclin D1, Mcl-1 and survivin). Manu A decreased the protein levels of BID, Bcl-xL and PARP while it increased Bax levels. Manu A caused depolarization of the mitochondrial membrane with induction of CHOP, DR4 and DR5. Our results demonstrated that Manu A exerted anticancer effects by inducing apoptosis via inhibition of the Sp1-related signaling pathway in human MPM.
authors.affiliation: Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 534-729, Republic of Korea.
authors.forename: Ka Hwi
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Dental Pharmacology, School of Dentistry and Institute of Oral Bioscience, BK21 Plus, Chonbuk National University, Jeonju 651-756, Republic of Korea.
authors.forename: Jung-Il
authors.initials: JI
authors.lastname: Chae
authors.affiliation: Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 534-729, Republic of Korea.
authors.forename: Hana
authors.initials: H
authors.lastname: Oh
authors.affiliation: Department of Dental Pharmacology, School of Dentistry and Institute of Oral Bioscience, BK21 Plus, Chonbuk National University, Jeonju 651-756, Republic of Korea.
authors.forename: Jin Hyoung
authors.initials: JH
authors.lastname: Cho
authors.affiliation: Department of Dental Pharmacology, School of Dentistry and Institute of Oral Bioscience, BK21 Plus, Chonbuk National University, Jeonju 651-756, Republic of Korea.
authors.forename: Ra-Ham
authors.initials: RH
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 534-729, Republic of Korea.
authors.forename: Goo
authors.initials: G
authors.lastname: Yoon
authors.affiliation: Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 534-729, Republic of Korea.
authors.forename: Seung-Sik
authors.initials: SS
authors.lastname: Cho
authors.affiliation: College of Pharmacy, Keimyung University, Dalseo-gu, Daegu 704-701, Republic of Korea.
authors.forename: Young-Sik
authors.initials: YS
authors.lastname: Cho
authors.affiliation: The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan 450001, P.R. China.
authors.forename: Mee-Hyun
authors.initials: MH
authors.lastname: Lee
authors.affiliation: The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan 450001, P.R. China.
authors.forename: Kangdong
authors.initials: K
authors.lastname: Liu
authors.affiliation: Division of Animal Genomics and Bioinformatics, National Institute of Animal Science, Rural Development Administration, Suwon 441-706, Republic of Korea.
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 534-729, Republic of Korea.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Shim
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000037:antagonists & inhibitors; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors; D008175:Lung Neoplasms / Q000188:drug therapy*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008654:Mesothelioma / Q000188:drug therapy*; D000086002:Mesothelioma, Malignant; D008928:Mitochondria / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors; D010997:Pleural Neoplasms / Q000188:drug therapy*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011090:Polyenes / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D000077022:Survivin; D051742:Transcription Factor CHOP / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D017304:Annexin A5; C494811:BCL2L1 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C107489:BIRC5 protein, human; C530104:CCND1 protein, human; C497249:DDIT3 protein, human; D051034:Inhibitor of Apoptosis Proteins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D016329:Sp1 Transcription Factor; D000077022:Survivin; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019938:Cyclin D1; D051742:Transcription Factor CHOP; D011065:Poly(ADP-ribose) Polymerases; C054474:manumycin