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Targeting ceramide synthase 6–dependent metastasis-prone phenotype in lung cancer cells
Motoshi Suzuki, … , Mamoru Kyogashima, Takashi Takahashi
Motoshi Suzuki, … , Mamoru Kyogashima, Takashi Takahashi
Published December 7, 2015
Citation Information: J Clin Invest. 2016;126(1):254-265. https://doi.org/10.1172/JCI79775.
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Research Article Oncology Article has an altmetric score of 1

Targeting ceramide synthase 6–dependent metastasis-prone phenotype in lung cancer cells

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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

Motoshi Suzuki, Ke Cao, Seiichi Kato, Yuji Komizu, Naoki Mizutani, Kouji Tanaka, Chinatsu Arima, Mei Chee Tai, Kiyoshi Yanagisawa, Norie Togawa, Takahiro Shiraishi, Noriyasu Usami, Tetsuo Taniguchi, Takayuki Fukui, Kohei Yokoi, Keiko Wakahara, Yoshinori Hasegawa, Yukiko Mizutani, Yasuyuki Igarashi, Jin-ichi Inokuchi, Soichiro Iwaki, Satoshi Fujii, Akira Satou, Yoko Matsumoto, Ryuichi Ueoka, Keiko Tamiya-Koizumi, Takashi Murate, Mitsuhiro Nakamura, Mamoru Kyogashima, Takashi Takahashi

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Figure 4

Migration activity in association with ceramide synthesis and lamellipodia formation/membrane ruffling.

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Migration activity in association with ceramide synthesis and lamellipod...
(A) Ceramide concentrations were determined in LNM35 cells (mean ± SD; n = 3). The experiment was replicated, with similar results obtained. (B) Migration assays were performed in the presence and absence of 100 nM myriocin (Sigma-Aldrich) in LNM35 cells (mean ± SD; n = 4). The experiment was replicated, with similar results obtained. (C) Following siRNA treatment, migration activity was measured in the presence and absence of 1 μM C16:0 ceramide in LNM35 cells (mean ± SD; n = 4). The experiment was replicated, with similar results obtained. (D) Twelve hours after serum stimulation, LNM35 cells were fixed and stained by anti-RAC1 and anti-pPKCζ antibodies. Arrowheads indicate lamellipodia/ruffling structures. Scale bar: 10 μm. (E) The numbers of cells with RAC1-positive lamellipodia/ruffling structures were determined by counting more than 100 cells (mean ± SD). (F) Twelve hours after serum stimulation, RERF-LC-AI cells were fixed and stained with anti-RAC1. Arrowheads indicate lamellipodia/ruffling structures. Scale bar: 50 μm. Three independent experiments were performed. (G) The numbers of cells with RAC1-positive lamellipodia/ruffling structures were determined by counting more than 100 cells (mean ± SD).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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