title: The requirement of SEPT2 and SEPT7 for migration and invasion in human breast cancer via MEK/ERK activation.
abstract: Septins are a novel class of GTP-binding cytoskeletal proteins evolutionarily conserved from yeast to mammals and have now been found to play a contributing role in a broad range of tumor types. However, their functional importance in breast cancer remains largely unclear. Here, we demonstrated that pharmaceutical inhibition of global septin dynamics would greatly suppress proliferation, migration and invasiveness in breast cancer cell lines. We then examined the expression and subcellular distribution of the selected septins SEPT2 and SEPT7 in breast cancer cells, revealing a rather variable localization of the two proteins with cell cycle progression. To determine the role of both septins in mediating malignant behavior of cancer cells, we used RNA silencing to specifically deplete endogenous SEPT2 or SEPT7 in highly invasive breast cancer cell line MDA-MB-231. Our findings showed that SEPT2/7 depletion had virtually identical inhibitory effects on cellular proliferation, apoptosis, migration and invasion. Moreover, the opposite performance in migration and invasion was observed after enforced expression of SEPT2/7 in the same cell line. We further demonstrated MEK/ERK activation, but not other MAPKs and AKT, was positively correlated with the protein levels of SEPT2 and SEPT7. Additionally, in SEPT2/7-overexpressing cells, the MEK specific inhibitor U0126 was able to correct the high active status of MEK/ERK while normalizing the increased invasive behaviors of these cells. Taken together, these results strongly suggest that SEPT2 and SEPT7 are involved in breast carcinogenesis and may serve as valuable therapeutic targets for breast cancer.
authors.affiliation: Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, P.R.China.
authors.forename: Nianzhu
authors.initials: N
authors.lastname: Zhang
authors.affiliation: College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044 Liaoning, P.R.China.
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.affiliation: College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044 Liaoning, P.R.China.
authors.forename: Ning
authors.initials: N
authors.lastname: Fan
authors.affiliation: Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, P.R.China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, P.R.China.
authors.forename: Weijie
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Gynecology and Obstetrics, Dalian Municipal Central Hospital Affiliated to Dalian Medical University, Dalian, 116033, Liaoning, P.R.China.
authors.forename: Mingnan
authors.initials: M
authors.lastname: Zheng
authors.affiliation: The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, Liaoning, P.R.China.
authors.forename: Lingfei
authors.initials: L
authors.lastname: Ma
authors.affiliation: College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044 Liaoning, P.R.China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, P.R.China.|State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, P.R.China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
mesh_terms: D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology*; D002070:Butadienes / Q000494:pharmacology; D063646:Carcinogenesis / Q000473:pathology*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D058112:Septins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D002070:Butadienes; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D009570:Nitriles; D010671:Phenylurea Compounds; D011725:Pyridines; D034741:RNA, Small Interfering; C113580:U 0126; D051057:Proto-Oncogene Proteins c-akt; D020930:MAP Kinase Kinase Kinases; C000602252:SEPTIN2 protein, human; C113158:SEPTIN7 protein, human; D058112:Septins; C116093:N-(2-chloro-4-pyridyl)-N'-phenylurea
keywords: MAPK; breast cancer; forchlorfenuron; invasion; septin