title: Impacts of CD44 knockdown in cancer cells on tumor and host metabolic systems revealed by quantitative imaging mass spectrometry.
abstract: CD44 expressed in cancer cells was shown to stabilize cystine transporter (xCT) that uptakes cystine and excretes glutamate to supply cysteine as a substrate for reduced glutathione (GSH) for survival. While targeting CD44 serves as a potentially therapeutic stratagem to attack cancer growth and chemoresistance, the impact of CD44 targeting in cancer cells on metabolic systems of tumors and host tissues in vivo remains to be fully determined. This study aimed to reveal effects of CD44 silencing on alterations in energy metabolism and sulfur-containing metabolites in vitro and in vivo using capillary electrophoresis-mass spectrometry and quantitative imaging mass spectrometry (Q-IMS), respectively. In an experimental model of xenograft transplantation of human colon cancer HCT116 cells in superimmunodeficient NOG mice, snap-frozen liver tissues containing metastatic tumors were examined by Q-IMS. As reported previously, short hairpin CD44 RNA interference (shCD44) in cancer cells caused significant regression of tumor growth in the host liver. Under these circumstances, the CD44 knockdown suppressed polyamines, GSH and energy charges not only in metastatic tumors but also in the host liver. In culture, HCT116 cells treated with shCD44 decreased total amounts of methionine-pool metabolites including spermidine and spermine, and reactive cysteine persulfides, suggesting roles of these metabolites for cancer growth. Collectively, these results suggest that CD44 expressed in cancer accounts for a key regulator of metabolic interplay between tumor and the host tissue.
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Ohmura
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Hishiki
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; MS Business Unit, Shimadzu Corporation, Kyoto 604-8511, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nakanishi
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kubo
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan; Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tsuchihashi
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Tamada
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Sakino
authors.initials: S
authors.lastname: Toue
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; Japan Science and Technology Agency, Exploratory Research for Advanced Technology, Suematsu Gas Biology Project, Tokyo 160-8582, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Kabe
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; Japan Science and Technology Agency, Exploratory Research for Advanced Technology, Suematsu Gas Biology Project, Tokyo 160-8582, Japan. Electronic address: gasbiology@z6.keio.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
mesh_terms: D000818:Animals; D003545:Cysteine / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D055442:Metabolome / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D055432:Metabolomics; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D018960:Hyaluronan Receptors; D034741:RNA, Small Interfering; D003545:Cysteine
keywords: Cancer; Polyamines; Reactive cysteine persulfides; Remethylation; Transsulfuration; xCT