Targeting ceramide synthase 6-dependent metastasisprone phenotype in lung cancer cells

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 InokuchiSoichiro Iwaki, Satoshi Fujii, Akira Satou, Yoko Matsumoto, Ryuichi Ueoka, Keiko Tamiya-Koizumi, Takashi Murate, Mitsuhiro Nakamura, Mamoru Kyogashima, Takashi Takahashi

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)254-265
Number of pages12
JournalJournal of Clinical Investigation
Volume126
Issue number1
DOIs
Publication statusPublished - 04-01-2016

Fingerprint

Lung Neoplasms
Phenotype
Ceramides
Non-Small Cell Lung Carcinoma
Sphingolipids
Pseudopodia
ceramide glucosyltransferase
Cell Movement
Neoplasms
Cell Death
Neoplasm Metastasis
Dimyristoylphosphatidylcholine
Glycogen Synthase
dihydroceramide desaturase
N-(alpha-hydroxyoctadecanoyl)phytosphingosine
MicroRNAs
Liposomes
Homeostasis
Maintenance
Apoptosis

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Suzuki, Motoshi ; Cao, Ke ; Kato, Seiichi ; Komizu, Yuji ; Mizutani, Naoki ; Tanaka, Kouji ; Arima, Chinatsu ; Chee Tai, Mei ; Yanagisawa, Kiyoshi ; Togawa, Norie ; Shiraishi, Takahiro ; Usami, Noriyasu ; Taniguchi, Tetsuo ; Fukui, Takayuki ; Yokoi, Kohei ; Wakahara, Keiko ; Hasegawa, Yoshinori ; Mizutani, Yukiko ; Igarashi, Yasuyuki ; Inokuchi, Jin Ichi ; Iwaki, Soichiro ; Fujii, Satoshi ; Satou, Akira ; Matsumoto, Yoko ; Ueoka, Ryuichi ; Tamiya-Koizumi, Keiko ; Murate, Takashi ; Nakamura, Mitsuhiro ; Kyogashima, Mamoru ; Takahashi, Takashi. / Targeting ceramide synthase 6-dependent metastasisprone phenotype in lung cancer cells. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 1. pp. 254-265.
@article{f4f7ac0bb0df44d2a73491405336a52b,
title = "Targeting ceramide synthase 6-dependent metastasisprone 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.",
author = "Motoshi Suzuki and Ke Cao and Seiichi Kato and Yuji Komizu and Naoki Mizutani and Kouji Tanaka and Chinatsu Arima and {Chee Tai}, Mei and Kiyoshi Yanagisawa and Norie Togawa and Takahiro Shiraishi and Noriyasu Usami and Tetsuo Taniguchi and Takayuki Fukui and Kohei Yokoi and Keiko Wakahara and Yoshinori Hasegawa and Yukiko Mizutani and Yasuyuki Igarashi and Inokuchi, {Jin Ichi} and Soichiro Iwaki and Satoshi Fujii and Akira Satou and Yoko Matsumoto and Ryuichi Ueoka and Keiko Tamiya-Koizumi and Takashi Murate and Mitsuhiro Nakamura and Mamoru Kyogashima and Takashi Takahashi",
year = "2016",
month = "1",
day = "4",
doi = "10.1172/JCI79775",
language = "English",
volume = "126",
pages = "254--265",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "1",

}

Suzuki, M, Cao, K, Kato, S, Komizu, Y, Mizutani, N, Tanaka, K, Arima, C, Chee Tai, M, Yanagisawa, K, Togawa, N, Shiraishi, T, Usami, N, Taniguchi, T, Fukui, T, Yokoi, K, Wakahara, K, Hasegawa, Y, Mizutani, Y, Igarashi, Y, Inokuchi, JI, Iwaki, S, Fujii, S, Satou, A, Matsumoto, Y, Ueoka, R, Tamiya-Koizumi, K, Murate, T, Nakamura, M, Kyogashima, M & Takahashi, T 2016, 'Targeting ceramide synthase 6-dependent metastasisprone phenotype in lung cancer cells', Journal of Clinical Investigation, vol. 126, no. 1, pp. 254-265. https://doi.org/10.1172/JCI79775

Targeting ceramide synthase 6-dependent metastasisprone phenotype in lung cancer cells. / Suzuki, Motoshi; Cao, Ke; Kato, Seiichi; Komizu, Yuji; Mizutani, Naoki; Tanaka, Kouji; Arima, Chinatsu; Chee Tai, Mei; Yanagisawa, Kiyoshi; Togawa, Norie; Shiraishi, Takahiro; Usami, Noriyasu; Taniguchi, Tetsuo; Fukui, Takayuki; Yokoi, Kohei; Wakahara, Keiko; Hasegawa, Yoshinori; Mizutani, Yukiko; Igarashi, Yasuyuki; Inokuchi, Jin Ichi; Iwaki, Soichiro; Fujii, Satoshi; Satou, Akira; Matsumoto, Yoko; Ueoka, Ryuichi; Tamiya-Koizumi, Keiko; Murate, Takashi; Nakamura, Mitsuhiro; Kyogashima, Mamoru; Takahashi, Takashi.

In: Journal of Clinical Investigation, Vol. 126, No. 1, 04.01.2016, p. 254-265.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Targeting ceramide synthase 6-dependent metastasisprone phenotype in lung cancer cells

AU - Suzuki, Motoshi

AU - Cao, Ke

AU - Kato, Seiichi

AU - Komizu, Yuji

AU - Mizutani, Naoki

AU - Tanaka, Kouji

AU - Arima, Chinatsu

AU - Chee Tai, Mei

AU - Yanagisawa, Kiyoshi

AU - Togawa, Norie

AU - Shiraishi, Takahiro

AU - Usami, Noriyasu

AU - Taniguchi, Tetsuo

AU - Fukui, Takayuki

AU - Yokoi, Kohei

AU - Wakahara, Keiko

AU - Hasegawa, Yoshinori

AU - Mizutani, Yukiko

AU - Igarashi, Yasuyuki

AU - Inokuchi, Jin Ichi

AU - Iwaki, Soichiro

AU - Fujii, Satoshi

AU - Satou, Akira

AU - Matsumoto, Yoko

AU - Ueoka, Ryuichi

AU - Tamiya-Koizumi, Keiko

AU - Murate, Takashi

AU - Nakamura, Mitsuhiro

AU - Kyogashima, Mamoru

AU - Takahashi, Takashi

PY - 2016/1/4

Y1 - 2016/1/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84956617449&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84956617449&partnerID=8YFLogxK

U2 - 10.1172/JCI79775

DO - 10.1172/JCI79775

M3 - Article

C2 - 26650179

AN - SCOPUS:84956617449

VL - 126

SP - 254

EP - 265

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 1

ER -