Molecular mechanisms of adaptive response of cancer cells to deprivation of both oxygen and nutrient

2009 Fiscal Year Final Research Report

• Project/Area Number: 17013087
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East
• Principal Investigator: ESUMI Hiroyasu National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East, 東病院、臨床開発センター, 院長 (70160364)
• Project Period (FY): 2005 – 2009
• Keywords: 低酸素 / 腫瘍血流 / エネルギー代謝 / 栄養欠乏 / ARK5

Research Abstract

Molecular and biochemical mechanisms of adaptive responses of cancer cells to deprivation of both oxygen and nutrient, which mimics tumor microenvironment of hypovascular tumors have been analyzed. In this series of experiments we have found following. 1)Tumor cells especially those from hypovascular tumor show resistance to hypoglycemia and even normal cells can be converted resistant to glucose deprivation by hypoxic condition. 2)AMPK AKT and AMPK-related kinases are involved in the response. 3)These molecules are involved in invasion and metastasis. 4)Under deprivation of nutrient and oxygen, autophagy is involved in cell survival. 5)Anaerobic energy production through fumarate respiration was found to be induced and operated by deprivation of both oxygen and glucose. 6)The metabolomic analysis of human cancer tissues strongly suggested anaerobic energy production through fumarate respiration. The present results opened a way to develop a novel strategy to treat cancer by targeting cancer cells' adaptation to their microenvironment.

Research Products

• [Journal Article] Mitochondrial inhibitors show preferential cytotoxicity to human pancreatic cancer PANC-1 cells under glucose-deprived conditions. (2010)
  • Author(s): Momose I, Ohba S, Tatsuda D, Kawada M, Masuda T, Tsujiuchi G, Yamori T, Esumi H, Ikeda D.
  • Journal Title: Biochem Biophys Res Commun. 392(3) Pages: 460-6
• [Journal Article] Autophagy and cancer: Dynamism of the metabolism of tumor cells and tissues. (2009)
  • Author(s): Tsuchihara K, Fujii S, Esumi H.
  • Journal Title: Cancer Lett. 278(2) Pages: 130-8
• [Journal Article] Massive transcriptional start site analysis of human genes in hypoxia cells. (2009)
  • Author(s): Tsuchihara K, Suzuki Y, Wakaguri H, Irie T, Tanimoto K, Hashimoto S, Matsushima K, Mizushima-Sugano J, Yamashita R, Nakai, K, Bentley D, Esumi H, Sugano S.
  • Journal Title: Nucleic Acids Res. 37(7) Pages: 2249-63
• [Journal Article] Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis Time-of-Flight mass spectrometry. (2009)
  • Author(s): Hirayama A, Kami K, Sugimoto M, Sugawara M, Toki N, Onozuka H, Kinoshita T, Saito N, Ochiai A, Tomita M, Esumi H, Soga T.
  • Journal Title: Cancer Res 69(11) Pages: 4918-25
• [Journal Article] Chemical constituents of propolis from myanmar and their preferential cytotoxicity against a human pancreatic cancer cell line. (2009)
  • Author(s): Li F, Awale S, Zhang H, Tezuka Y, Esumi H, Kadota S.
  • Journal Title: J Nat Prod. 72(7) Pages: 1283-7
• [Journal Article] Regulation of succinate-ubiquinone reductase and fumarate reductase activities in human complex II by phosphorylation of its flavoprotein subunit. (2009)
  • Author(s): Tomitsuka E, Kita K, Esumi H.
  • Journal Title: Proc Jpn Acad. 85(7) Pages: 258-65
• [Journal Article] Cytotoxic constituents of soymida febrifuga from myanmar. (2009)
  • Author(s): Awale S, Miyamoto T, Linn TZ, Li F, Win NN, Tezuka Y, Esumi H, Kadota S.
  • Journal Title: J Nat Prod. 72(9) Pages: 1631-6
• [Journal Article] Induction of necrosis in human myeloma cells by kigamisin. (2008)
  • Author(s): Nakamura M, Esumi H, Jin L, Mitsuya H, Hata H.
  • Journal Title: Anticancer Res. 28(1A) Pages: 37-43
• [Journal Article] Constituents of Brazilian red propolis and their preferential cytotoxic activity against huma cancer cell line in nutrient-deprived condition. (2008)
  • Author(s): Awale S, Li F, Onozuka H, Esumi H, Tezuka Y, Kadota S.
  • Journal Title: Bioorganic & Medicinal Chemistry. 16(1) Pages: 181-9
• [Journal Article] Novel anticancer agents, kayeassamins A and B from the flower of Kayea assamica of Myanmar. (2008)
  • Author(s): Win NN, Awale S, Esumi H, Tezuka Y, Kadota S.
  • Journal Title: Bioorg Med Chem Lett. 18(16) Pages: 4688-91
• [Journal Article] Novel anticancer agents, kayeassamins C-I from the flower of Kayea assamica of Myanmar. (2008)
  • Author(s): Win NN, Awale S, Esumi H, Tezuka Y, Kadota S.
  • Journal Title: Bioorg Med Chem. 16(18) Pages: 8653-60
• [Journal Article] Autophagy is activated in pancreatic cancer cells and correlates with poor patient outcome. (2008)
  • Author(s): Fujii S, Mitsunaga S, Yamazaki M, Hasebe T, Ishii G, Kojima M, Kinoshita T, Ueno T, Esumi H, Ochiai A.
  • Journal Title: Cancer Sci. 99(9) Pages: 1813-9
• [Journal Article] Panduratins D-I, novel secondary metabolites from rhizomes of Boesenbergia pandurata. (2008)
  • Author(s): Win NN, Awale S, Esumi H, Tezuka Y, Kadota S.
  • Journal Title: Chem Pharm Bull (Tokyo). 56(4) Pages: 491-6
• [Journal Article] Nuclear localization of SNARK; its impact on gene expression. (2008)
  • Author(s): Kuga W, Tsuchihara K, Ogura T, Kanehara S, Saito M, Suzuki A, Esumi H.
  • Journal Title: Biochem Biophys Res Commun. 377(4) Pages: 1062-6
• [Journal Article] Bioactive Secondary Metabolites from Boesenbergia pandurata of Myanmar and Their Preferential Cytotoxicity against Human Pancreatic Cancer PANC-1 Cell Line in Nutrient-Deprived Medium. (2007)
  • Author(s): Win NN, Awale S, Esumi H, Tezuka Y, Kadota S.
  • Journal Title: J Nat Prod. 70(10) Pages: 1582-7
• [Journal Article] Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation. (2007)
  • Author(s): Sato K, Tsuchihara K, Fujii S, Sugiyama M, Goya T, Atomi Y, Ueno T, Ochiai A, Esumi H.
  • Journal Title: Cancer Res. 67(20) Pages: 9677-84
• [Journal Article] c-Maf expression in angioimmunoblastic T-cell lymphoma. (2007)
  • Author(s): Murakami I Y, Yatabe Y, Sakaguchi T, Sasaki E, Yamashita Y, Morito N, Yoh K, Fujioka Y, Matsuno F, Hata H, Mitsuya H, Imagawa S, Suzuki A, Esumi H, Sakai M, Takahashi S.
  • Journal Title: Am J Surg Pathol 31(11) Pages: 1695-702
• [Journal Article] Diterpenes from "Pini Resina" and their preferential cytotoxic activity under nutrient-deprived condition. (2006)
  • Author(s): Zaidi SF, Awale S, Kalauni SK, Tezuka Y, Esumi H, Kadota S.
  • Journal Title: Planta Med 72(13) Pages: 1231-4
• [Journal Article] Antitumor effect of kigamicin D on mouse tumor models. (2006)
  • Author(s): Masuda T, Ohba S, Kawada M, Osono M, Ikeda D, Esumi H, Kunimoto S.
  • Journal Title: J Antibiot (Tokyo) 59 Pages: 209-14
• [Journal Article] NDR2 acts as the upstream kinase of ARK5 during insulin-like growth factor-1 signaling. (2006)
  • Author(s): Suzuki A, Ogura T, Esumi H.
  • Journal Title: J Biol Chem 281 Pages: 13915-21
• [Journal Article] Angelmarin, a novel anti-cancer agent able to eliminate the tolerance of cancer cells to nutrient starvation. (2006)
  • Author(s): Awale S, Nakashima EM, Kalauni SK, Tezuka Y, Kurashima Y, Lu J, Esumi H, Kadota S.
  • Journal Title: Bioorg Med Chem Lett 16 Pages: 581-3
• [Journal Article] Identification of arctigenin as an antitumor agent having the ability to eliminate the tolerance of cancer cells to nutrient starvation. (2006)
  • Author(s): Awale S, Lu J, Kalauni SK, Kurashima Y, Tezuka Y, Kadota S, Esumi H.
  • Journal Title: Cancer Res 66 Pages: 1751-7
• [Journal Article] Overexpression of c-Maf contributes to T-cell lymphoma in both mice and human. (2006)
  • Author(s): Morito N, Yoh K, Fujioka Y, Nakano T, Shimohata H, Hashimoto Y, Yamada A, Maeda A, Matsuno F, Hata H, Suzuki A, Imagawa S, Mitsuya H, Esumi H, Koyama A, Yamamoto M, Mori N, Takahashi S.
  • Journal Title: Cancer Res 66 Pages: 812-9
• [Journal Article] Chemopreventive effect of peroxisome proliferators activated receptor gamma on gastric carcinogenesis in mice. (2005)
  • Author(s): Lu J, Imamura K, Nomura S, Mafune K, Nakajima A, Kadowaki T, Kubota N, Terauchi Y, Ishii G., Ochiai A, Esumi H, Kaminishi M.
  • Journal Title: Cancer Res. 65(11) Pages: 4769-74
• [Journal Article] Overexpression of 6-phosphofructo-2-kinase/ fructose-2, 6-bisphosphatase-4 in the human breast and colon malignant tumors. (2005)
  • Author(s): Minchenko OH, Ochiai A, Opentanova IL, Ogura T, Minchenko DO, Caro J, Komisarenko SV, Esumi H.
  • Journal Title: Biochimie. 87(11) Pages: 1005-10
• [Journal Article] ARK5 is transcriptionally regulated by the Large-MAF Family and mediates IGF-1-induced cell invasion in multiple myeloma; ARK5 is a new molecular determinant of malignant multiple myeloma. (2005)
  • Author(s): Suzuki A, Iida S, Kato-Uranishi M, Tajima E, Zhan F, Hanamura I, Huang Y, Ogura T, Takahashi S, Ueda R, Barlogie B, Shaughnessy J Jr., Esumi H.
  • Journal Title: Oncogene 24 Pages: 6936-44
• [Journal Article] Splice isoform of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase-4: expression and hypoxic regulation. (2005)
  • Author(s): Minchenko OH, Ogura T, Opentanova IL, Minchenko DO, Esumi H.
  • Journal Title: Mol Cell Biochem. 280(1-2) Pages: 227-34
• [Patent(Industrial Property Rights)] アクチゲニン高含有ゴボウシエキス及びその製造方法 (2009)
  • Inventor(s): 江角浩安・三好千香・門田重利・山本恵一
  • Industrial Property Rights Holder: 国立がんセンター・クラシエ製薬・富山大学
  • Industrial Property Number: 特許・2009-079590
  • Filing Date: 2009-03-27
• [Patent(Industrial Property Rights)] 新規抗腫瘍物質アルキルクマリン類とその用途 (2008)
  • Inventor(s): 江角浩安・三好千香・門田重利・Suresh Awale・手塚康弘
  • Industrial Property Rights Holder: ヒューマンサイエンス振興財団
  • Industrial Property Number: 特許・2008-138555
  • Filing Date: 2008-05-27
• [Patent(Industrial Property Rights)] 抗腫瘍剤 (2005)
  • Inventor(s): 江角浩安・倉島由紀子・門田重利・Suresh Awale
  • Industrial Property Rights Holder: 国立がんセンター・富山医科薬科大学
  • Industrial Property Number: 特許・2005-221360
  • Filing Date: 2005-09-28