The involvement of sphingolipid metabolism in anti cancer drug sensitivity of malignant cells

2013 Fiscal Year Final Research Report

• Project/Area Number: 23590667
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Nagoya University
• Principal Investigator: MURATE Takashi 名古屋大学, 医学(系)研究科(研究院), 教授 (30239537)
• Co-Investigator(Kenkyū-buntansha): KIJIMA Tetsuhito 名古屋大学, 大学院医学系研究科, 教授 (40161913) ; TAKAGI Akira 名古屋大学, 大学院医学系研究科, 助教 (30135371) ; SUZUKI Motoshi 名古屋大学, 大学院医学系研究科, 講師 (80236017)
• Project Period (FY): 2011 – 2013
• Keywords: sphingolipid / metabolic enzyme / gene expression / anti-cancer drug / human cancer cell lines

Research Abstract

In the first year, we analyzed the mechanism of GAP43 expression during GDNF treatment of a neuronal cel line, TGW. Our analysis revealed that GDNF induced SPHK1 expression through RET receptor, followed by S1P secretion and S1P1/3 receptor activation. We further found that GAP43 expression was due to the increased CREB transcription factor binding to the GAP43 5'-promoter region.
Next, we analyzed the regulatory mechanism of neutral sphingomyelinase 2 and neutral ceramidase with all trans retinoid acid (ATRA). Our analysis revealed that activated Sp1 transcription factor and decreased GATA2 were responsive for the observed changes in treated MCF-7 and SH-SY5Y cells, respectively.
In the third year, we analyzed the mechanism of high SPHK1 expression of mouse Friend cells. We found that c-MYB is responsible for this overepression and that chemical inducer, HMBA, rapidly decreased SPHK1 expression, which is at least partially responsible for this terminal differentiation process.

Research Products

• [Journal Article] Sphingosine kinase 1 plays a role in the upregulation of CD44 expression through extracellular signal-regulated kinase signaling in human colon cancer cells (2013)
  • Author(s): Kawahara S, Otsuji Y, Nakamura M, Murakami M, Murate T, Matsunaga T, Kanoh H, Seishima M, Banno Y, Hara A
  • Journal Title: Anticancer Drugs Volume: 24(5) Pages: 473-83
  • DOI: 10.1097/CAD.0b013e32835f705f
  • Peer Reviewed
• [Journal Article] Sphingosine kinase 1 expression is downregulated during differentiation of Friend cells due to decreased c-MYB (2013)
  • Author(s): Mizutani N, Kobayashi M, Sobue S, Ichihara M, Ito H, Tanaka K, Iwaki S, Fujii S, Ito Y, Tamiya-Koizumi K, Takagi A, Kojima T, Naoe T, Suzuki M, Nakamura M, Banno Y, Nozawa Y, Murate T
  • Journal Title: Biochim Biophys Acta Volume: 1833(5) Pages: 1006-16
  • DOI: 10.1016/j.bbamcr.2013.01.001
  • Peer Reviewed
• [Journal Article] Transcriptional regulation of neutral sphingomyelinase 2 in all-trans retinoic acid-treated human breast cancer cell line, MCF-7 (2012)
  • Author(s): Ito H, Tanaka K, Hagiwara K, Kobayashi M, Hoshikawa A, Mizutani N, Takagi A, Kojima T, Sobue S, Ichihara M, Suzuki M, Tamiya-Koizumi K, Nakamura M, Banno Y, Nozawa Y, Murate T
  • Journal Title: J Biochem Volume: 151(6) Pages: 599-610
  • DOI: 10.1093/jb/mvs037
  • Peer Reviewed
• [Journal Article] Role of down-regulated neutral ceramidase during all-trans retinoic acid-induced neuronal differentiation in SH-SY5Y neuroblastoma cells (2012)
  • Author(s): Tanaka K, Tamiya-Koizumi K, Hagiwara K, Ito H, Takagi A, Kojima T, Suzuki M, Iwaki S, Fujii S, Nakamura M, Banno Y, Kannagi R, Tsurumi T, Kyogashima M, Murate T
  • Journal Title: J Biochem Volume: 151(6) Pages: 611-20
  • DOI: 10.1093/jb/mvs033
  • Peer Reviewed
• [Journal Article] Hybrid liposomes affect cellular lipid constituents and caveolae structures (2012)
  • Author(s): Cao K, Tanaka K, Komizu Y, Tamiya-Koizumi K, Murate T, Ueoka R, Kyogashima M, Usukura J, Takahashi T, Suzuki M
  • Journal Title: Bioorg Med Chem Lett Volume: 22(4) Pages: 1731-3
  • DOI: 10.1016/j.bmcl.2011.12.093
  • Peer Reviewed
• [Journal Article] Sphingosine kinase 1/S1P pathway involvement in the GDNF-induced GAP43 transcription (2011)
  • Author(s): Murate T
  • Journal Title: J Cell Biochem Volume: 112(11) Pages: 3449-58
  • DOI: 10.1002/jcb.23275
  • Peer Reviewed
• [Presentation] The mechanism of cytotoxicity by resveratrol against human leukemia cell lines (2013)
  • Author(s): Omori Y, Mizutani N, Inoue M, Nishida Y, Suzuki M, Koizumi K, Takagi A, Kojima T, Iwaki S, Fujii S, Nakamura M, Nozawa Y, Murate T
  • Organizer: 7^<th> International Conference of Ceramide
  • Place of Presentation: Montauk, NY. USA
  • Year and Date: 2013-10-22
• [Presentation] Regulatory mechanism of SPHK2 expresssion in colon cancer cell lines (2013)
  • Author(s): Mizutani N, Inoue M, Nishida Y, Omori Y, Suzuki M, Koizumi K, Takagi A, Kojima T, Iwaki S, Fujii S, Nakamura M, Banno Y, Nozawa Y, Murate T
  • Organizer: 7^<th> International Conference of Ceramide
  • Place of Presentation: Montauk, NY. USA
  • Year and Date: 2013-10-21