2-Deoxy-L-ribose inhibits the invasion of thymidine phosphorylase-overexpressing tumors by suppressing matrix metalloproteinase-9
Yuichi Nakajima
Department of Molecular Oncology, Field of Oncology, Course of Advanced Therapeutics,Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Japan
Search for more papers by this authorMisako Haraguchi
Department of Molecular Oncology, Field of Oncology, Course of Advanced Therapeutics,Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Japan
Search for more papers by this authorTatsuhiko Furukawa
Department of Molecular Oncology, Field of Oncology, Course of Advanced Therapeutics,Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Japan
Search for more papers by this authorMasatatsu Yamamoto
Department of Molecular Oncology, Field of Oncology, Course of Advanced Therapeutics,Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Japan
Search for more papers by this authorHayao Nakanishi
Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-ku, Nagoya, Japan
Search for more papers by this authorMasae Tatematsu
Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-ku, Nagoya, Japan
Search for more papers by this authorCorresponding Author
Shin-ichi Akiyama
Department of Molecular Oncology, Field of Oncology, Course of Advanced Therapeutics,Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Japan
Fax: 099-265-9687.
Department of Molecular Oncology, Field of Oncology, Course of Advanced Therapeutics, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, JapanSearch for more papers by this authorYuichi Nakajima
Department of Molecular Oncology, Field of Oncology, Course of Advanced Therapeutics,Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Japan
Search for more papers by this authorMisako Haraguchi
Department of Molecular Oncology, Field of Oncology, Course of Advanced Therapeutics,Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Japan
Search for more papers by this authorTatsuhiko Furukawa
Department of Molecular Oncology, Field of Oncology, Course of Advanced Therapeutics,Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Japan
Search for more papers by this authorMasatatsu Yamamoto
Department of Molecular Oncology, Field of Oncology, Course of Advanced Therapeutics,Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Japan
Search for more papers by this authorHayao Nakanishi
Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-ku, Nagoya, Japan
Search for more papers by this authorMasae Tatematsu
Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-ku, Nagoya, Japan
Search for more papers by this authorCorresponding Author
Shin-ichi Akiyama
Department of Molecular Oncology, Field of Oncology, Course of Advanced Therapeutics,Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Japan
Fax: 099-265-9687.
Department of Molecular Oncology, Field of Oncology, Course of Advanced Therapeutics, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, JapanSearch for more papers by this authorAbstract
Thymidine phosphorylase (TP), an enzyme involved in pyrimidine metabolism, is identical with an angiogenic factor, platelet-derived endothelial cell growth factor. 2-Deoxy-D-ribose (D-dRib), the degradation product of thymidine generated by TP activity, has been suggested to be a downstream mediator of TP function. 2-Deoxy-L-ribose (L-dRib), a stereoisomer of D-dRib, inhibited the promotion of angiogenesis, tumor growth and metastasis by TP. In our study, we have shown that nude mice inoculated with TP-overexpressing KB/TP cells had shorter survival times than those injected with control KB/CV cells. KB/TP tumors were also more highly invasive than KB/CV tumors in mice. The expression levels of matrix metalloproteinase (MMP)-9 in KB/TP tumors were significantly higher than those in KB/CV tumors. L-dRib and a TP inhibitior, TPI, extended the survival period of KB/TP tumor-bearing mice. L-dRib also reduced MMP-9 mRNA levels in KB/TP tumors. Furthermore, L-dRib suppressed the mRNA level of MMP-9 in cultured KB/TP cells, and the invasive activity of the cells. L-dRib may be useful for the suppression of invasion of TP-expressing tumor cells. © 2006 Wiley-Liss, Inc.
References
- 1 Akiyama S, Furukawa T, Sumizawa T, Takebayashi Y, Nakajima Y, Shimaoka S, Haraguchi M. The role of thymidine phosphorylase, an angiogenic enzyme, in tumor progression. Cancer Sci 2004; 95: 851–7.
- 2 Takebayashi Y, Yamada K, Miyadera K, Sumizawa T, Furukawa T, Kinoshita F, Aoki D, Okumura H, Yamada Y, Akiyama S, Aikou T. The activity and expression of thymidine phosphorylase in human solid tumours. Eur J Cancer A 1996; 32: 1227–32.
- 3 Imazono Y, Takebayashi Y, Nishiyama K, Akiba S, Miyadera K, Yamada Y, Akiyama S, Ohi Y. Correlation between thymidine phosphorylase expression and prognosis in human renal cell carcinoma. J Clin Oncol 1997; 15: 2570–8.
- 4 Takebayashi Y, Akiyama S, Akiba S, Yamada K, Miyadera K, Sumizawa T, Yamada Y, Murata F, Aikou T. Clinicopathologic and prognostic significance of an angiogenic factor, thymidine phosphorylase, in human colorectal carcinoma. J Natl Cancer Inst 1996; 88: 1110–7.
- 5
Saito S,
Tsuno N,
Nagawa H,
Sunami E,
Zhengxi J,
Osada T,
Kitayama J,
Shibata Y,
Tsuruo T,
Muto T.
Expression of platelet-derived endothelial cell growth factor correlates with good prognosis in patients with colorectal carcinoma.
Cancer
2000;
88:
42–9.
10.1002/(SICI)1097-0142(20000101)88:1<42::AID-CNCR7>3.0.CO;2-M CAS PubMed Web of Science® Google Scholar
- 6 Tsuji T, Sawai T, Yamashita H, Takeshita H, Nakagoe T, Shindou H, Fukuoka H, Yoshinaga M, Hidaka S, Yasutake T, Nagayasu T, Tagawa Y. Platelet-derived endothelial cell growth factor expression is an independent prognostic factor in colorectal cancer patients after curative surgery. Eur J Surg Oncol 2004; 30: 296–302.
- 7 Kitazono M, Takebayashi Y, Ishitsuka K, Takao S, Tani A, Furukawa T, Miyadera K, Yamada Y, Aikou T, Akiyama S. Prevention of hypoxia-induced apoptosis by the angiogenic factor thymidine phosphorylase. Biochem Biophys Res Commun 1998; 253: 797–803.
- 8 Mori S, Takao S, Ikeda R, Noma H, Mataki Y, Wang X, Akiyama S, Aikou T. Thymidine phosphorylase suppresses Fas-induced apoptotic signal transduction independent of its enzymatic activity. Biochem Biophys Res Commun 2002; 295: 300–5.
- 9 Jeung HC, Che XF, Haraguchi M, Furukawa T, Zheng CL, Sumizawa T, Rha SY, Roh JK, Akiyama S. Thymidine phosphorylase suppresses apoptosis induced by microtubule-interfering agents. Biochem Pharmacol 2005; 70: 13–21.
- 10
Shimaoka S,
Matsushita S,
Nitanda T,
Matsuda A,
Nioh T,
Suenaga T,
Nishimata Y,
Akiba S,
Akiyama S,
Nishimata H.
The role of thymidine phosphorylase expression in the invasiveness of gastric carcinoma.
Cancer
2000;
88:
2220–7.
10.1002/(SICI)1097-0142(20000515)88:10<2220::AID-CNCR4>3.0.CO;2-C CAS PubMed Web of Science® Google Scholar
- 11 Takao S, Takebayashi Y, Che X, Shinchi H, Natsugoe S, Miyadera K, Yamada Y, Akiyama S, Aikou T. Expression of thymidine phosphorylase is associated with a poor prognosis in patients with ductal adenocarcinoma of the pancreas. Clin Cancer Res 1998; 4: 1619–24.
- 12 O'Brien T, Cranston D, Fuggle S, Bicknell R, Harris AL. Different angiogenic pathways characterize superficial and invasive bladder cancer. Cancer Res 1995; 55: 510–3.
- 13 Jones A, Fujiyama C, Turner K, Cranston D, Williams K, Stratford I, Bicknell R, Harris AL. Role of thymidine phosphorylase in an in vitro model of human bladder cancer invasion. J Urol 2002; 167: 1482–6.
- 14 Takao S, Akiyama SI, Nakajo A, Yoh H, Kitazono M, Natsugoe S, Miyadera K, Fukushima M, Yamada Y, Aikou T. Suppression of metastasis by thymidine phosphorylase inhibitor. Cancer Res 2000; 60: 5345–8.
- 15 Sato J, Sata M, Nakamura H, Inoue S, Wada T, Takabatake N, Otake K, Tomoike H, Kubota I. Role of thymidine phosphorylase on invasiveness and metastasis in lung adenocarcinoma. Int J Cancer 2003; 106: 863–70.
- 16 Haraguchi M, Miyadera K, Uemura K, Sumizawa T, Furukawa T, Yamada K, Akiyama S, Yamada Y. Angiogenic activity of enzymes. Nature 1994; 368: 198.
- 17 Uchimiya H, Furukawa T, Okamoto M, Nakajima Y, Matsushita S, Ikeda R, Gotanda T, Haraguchi M, Sumizawa T, Ono M, Kuwano M, Kanzaki T, et al. Suppression of thymidine phosphorylase-mediated angiogenesis and tumor growth by 2-deoxy-L-ribose. Cancer Res 2002; 62: 2834–9.
- 18 Potter H, Weir L, Leder P. Enhancer-dependent expression of human kappa immunoglobulin genes introduced into mouse pre-B lymphocytes by electroporation. Proc Natl Acad Sci USA 1984; 81: 7161–5.
- 19 Matsushita S, Nitanda T, Furukawa T, Sumizawa T, Tani A, Nishimoto K, Akiba S, Miyadera K, Fukushima M, Yamada Y, Yoshida H, Kanzaki T, et al. The effect of a thymidine phosphorylase inhibitor on angiogenesis and apoptosis in tumors. Cancer Res 1999; 59: 1911–6.
- 20 Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, Simon R, Li Y, Robles AI, Chen Y, Ma ZC, Wu ZQ, et al. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med 2003; 9: 416–23.
- 21 Takahashi Y, Ellis LM, Mai M. The angiogenic switch of human colon cancer occurs simultaneous to initiation of invasion. Oncol Rep 2003; 10: 9–13.
- 22 Oh J, Takahashi R, Kondo S, et al. The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell 2001; 107: 789–800.
- 23 Sheu BC, Lien HC, Ho HN, Lin HH, Chow SN, Huang SC, Hsu SM. Increased expression and activation of gelatinolytic matrix metalloproteinases is associated with the progression and recurrence of human cervical cancer. Cancer Res 2003; 63: 6537–42.
- 24 Pepper MS. Role of the matrix metalloproteinase and plasminogen activator-plasmin systems in angiogenesis. Arterioscler Thromb Vasc Biol 2001; 21: 1104–17.
- 25 Opdenakker G, Van den Steen PE, Van Damme J. Gelatinase B: a tuner and amplifier of immune functions. Trends Immunol 2001; 22: 571–9.
- 26 Brown NS, Jones A, Fujiyama C, Harris AL, Bicknell R. Thymidine phosphorylase induces carcinoma cell oxidative stress and promotes secretion of angiogenic factors. Cancer Res 2000; 60: 6298–302.
- 27 Nakajima Y, Gotanda T, Uchimiya H, Furukawa T, Haraguchi M, Ikeda R, Sumizawa T, Yoshida H, Akiyama S. Inhibition of metastasis of tumor cells overexpressing thymidine phosphorylase by 2-deoxy-L-ribose. Cancer Res 2004; 64: 1794–801.
- 28 Hotchkiss KA, Ashton AW, Schwartz EL. Thymidine phosphorylase and 2-deoxyribose stimulate human endothelial cell migration by specific activation of the integrins α5β1 and αvβ3. J Biol Chem 2003; 278: 19272–9.
- 29 Sein TT, Thant AA, Hiraiwa Y, Amin AR, Sohara Y, Liu Y, Matsuda S, Yamamoto T, Hamaguchi M. A role for FAK in the Concanavalin A-dependent secretion of matrix metalloproteinase-2 and -9. Oncogene 2000; 19: 5539–42.
- 30 Seeliger H, Guba M, Koehl GE, Doenecke A, Steinbauer M, Bruns CJ, Wagner C, Frank E, Jauch KW, Geissler EK. Blockage of 2-deoxy-D-ribose-induced angiogenesis with rapamycin counteracts a thymidine phosphorylase-based escape mechanism available for colon cancer under 5-fluorouracil therapy. Clin Cancer Res 2004; 10: 1843–52.
- 31 Xia H, Nho RS, Kahm J, Kleidon J, Henke CA. Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a β1 integrin viability signaling pathway. J Biol Chem 2004; 279: 33024–34.
- 32 Kim D, Kim S, Koh H, Yoon SO, Chung AS, Cho KS, Chung J. Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. FASEB J 2001; 15: 1953–62.
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