title: Targeting ceramide synthase 6-dependent metastasis-prone phenotype in lung cancer cells.
abstract: Sphingolipids make up a family of molecules associated with an array of biological functions, including cell death and migration. Sphingolipids are often altered in cancer, though how these alterations lead to tumor formation and progression is largely unknown. Here, we analyzed non-small-cell lung cancer (NSCLC) specimens and cell lines and determined that ceramide synthase 6 (CERS6) is markedly overexpressed compared with controls. Elevated CERS6 expression was due in part to reduction of microRNA-101 (miR-101) and was associated with increased invasion and poor prognosis. CERS6 knockdown in NSCLC cells altered the ceramide profile, resulting in decreased cell migration and invasion in vitro, and decreased the frequency of RAC1-positive lamellipodia formation while CERS6 overexpression promoted it. In murine models, CERS6 knockdown in transplanted NSCLC cells attenuated lung metastasis. Furthermore, combined treatment with l-α-dimyristoylphosphatidylcholine liposome and the glucosylceramide synthase inhibitor D-PDMP induced cell death in association with ceramide accumulation and promoted cancer cell apoptosis and tumor regression in murine models. Together, these results indicate that CERS6-dependent ceramide synthesis and maintenance of ceramide in the cellular membrane are essential for lamellipodia formation and metastasis. Moreover, these results suggest that targeting this homeostasis has potential as a therapeutic strategy for CERS6-overexpressing NSCLC.
authors.forename: Motoshi
authors.initials: M
authors.lastname: Suzuki
authors.forename: Ke
authors.initials: K
authors.lastname: Cao
authors.forename: Seiichi
authors.initials: S
authors.lastname: Kato
authors.forename: Yuji
authors.initials: Y
authors.lastname: Komizu
authors.forename: Naoki
authors.initials: N
authors.lastname: Mizutani
authors.forename: Kouji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Arima
authors.forename: Mei Chee
authors.initials: MC
authors.lastname: Tai
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yanagisawa
authors.forename: Norie
authors.initials: N
authors.lastname: Togawa
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shiraishi
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Usami
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fukui
authors.forename: Kohei
authors.initials: K
authors.lastname: Yokoi
authors.forename: Keiko
authors.initials: K
authors.lastname: Wakahara
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Mizutani
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Igarashi
authors.forename: Jin-ichi
authors.initials: J
authors.lastname: Inokuchi
authors.forename: Soichiro
authors.initials: S
authors.lastname: Iwaki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujii
authors.forename: Akira
authors.initials: A
authors.lastname: Satou
authors.forename: Yoko
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Ueoka
authors.forename: Keiko
authors.initials: K
authors.lastname: Tamiya-Koizumi
authors.forename: Takashi
authors.initials: T
authors.lastname: Murate
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Nakamura
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kyogashima
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D004134:Dimyristoylphosphatidylcholine / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D035683:MicroRNAs / Q000502:physiology; D009362:Neoplasm Metastasis; D010641:Phenotype; D051049:Sphingosine N-Acyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: D002518:Ceramides; C534072:MIRN101 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C506123:CERS6 protein, human; D051049:Sphingosine N-Acyltransferase; D004134:Dimyristoylphosphatidylcholine