title: Salternamide A Suppresses Hypoxia-Induced Accumulation of HIF-1α and Induces Apoptosis in Human Colorectal Cancer Cells.
abstract: Hypoxia inducible factor-1α (HIF-1α) is an essential regulator of the cellular response to low oxygen concentrations, activating a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1α is overexpressed in various cancers and therefore represents a considerable chemotherapeutic target. Salternamide A (SA), a novel small molecule that is isolated from a halophilic Streptomyces sp., is a potent cytotoxic agent against a variety of human cancer cell lines. However, the mechanisms by which SA inhibits tumor growth remain to be elucidated. In the present study, we demonstrate that SA efficiently inhibits the hypoxia-induced accumulation of HIF-1α in a time- and concentration-dependent manner in various human cancer cells. In addition, SA suppresses the upstream signaling of HIF-1α, such as PI3K/Akt/mTOR, p42/p44 MAPK, and STAT3 signaling under hypoxic conditions. Furthermore, we found that SA induces cell death by stimulating G2/M cell cycle arrest and apoptosis in human colorectal cancer cells. Taken together, SA was identified as a novel small molecule HIF-1α inhibitor from marine natural products and is potentially a leading candidate in the development of anticancer agents.
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Korea. bdhiep90@snu.ac.kr.
authors.forename: Duc-Hiep
authors.initials: DH
authors.lastname: Bach
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Korea. yanberk@snu.ac.kr.
authors.forename: Seong-Hwan
authors.initials: SH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Korea. jyhong7876@daum.net.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Hong
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Korea. phj00@snu.ac.kr.
authors.forename: Hyen Joo
authors.initials: HJ
authors.lastname: Park
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Korea. sklee61@snu.ac.kr.
authors.forename: Dong-Chan
authors.initials: DC
authors.lastname: Oh
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Korea. sklee61@snu.ac.kr.
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D011090:Polyenes / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013302:Streptomyces / Q000378:metabolism; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011090:Polyenes; D053284:Polyunsaturated Alkamides; C000600890:salternamide A
keywords: HIF-1α; PI3K/Akt/mTOR; STAT3; cell death; p42/p44 MAPK; salternamide A (SA)