1990: B. Pharm. Sci., Faculty of Pharmaceutical Sciences, the University of Tokyo|
1995: Ph.D. (Doctor of Pharmaceutical Sciences), the University of Tokyo
1994-1995: Doctor Course Fellow: Fellowships of the Japan Society for the Promotion of Science for Japanese Junior Scientists
1995: Assistant Professor, Institute of Molecular and Cellular Biosciences, the University of Tokyo
2004: Associate Professor, Institute of Molecular and Cellular Biosciences, the University of Tokyo (Associate Professor, Graduate School of Medicine, the University of Tokyo)
2004: Associate Professor, Graduate School of Pharmaceutical Sciences, the University of Tokyo
2005: Associate Professor, Graduate School of Frontier Sciences, the University of Tokyo
2006: Chief, Division of Experimental Chemotherapy, Cancer Chemotherapy Center, JFCR
2008: Invited Professor (the University of Tokushima)
2010: Invited Professor (the University of Tokyo)
Faculty of Pharmaceutical Sciences, the University of Tokyo|
Graduate School of Pharmaceutical Sciences, Kyoto University
The Japanese Red Cross College of Nursing
Graduate School, The Japanese Red Cross College of Nursing
(1) Multidrug resistance and the reversing drugs|
One serious concern in cancer chemotherapy is emergence of acquired drug resistance in cancer cells. We have characterized biochemical function of P-glycoprotein, which is localized on the plasma membrane of resistant cells and exports a variety of unrelated anticancer drugs in an ATP-dependent manner. Because P-gp is involved in both acquired and intrinsic multidrug resistance (MDR), selective killing of cancer cells that express P-gp is very important. We have developed a novel quinoline derivative, MS-209, which inhibits both P-gp and MRP and is now in clinical trials.
(2) PDK1/Akt-mediated survival signals
The serine/threonine kinase Akt (also known as PKB or RAC-PK) is a key molecule for protecting cells from undergoing apoptosis. Several experiments have suggested that the Akt-mediated survival-signaling pathway is an attractive target for cancer chemotherapy. First, the Akt pathway is relatively inactive in resting cells; second, amplification of the akt gene occurs in some tumors; third, loss of the tumor suppressor PTEN gene is common in tumors and its loss constitutively activates Akt. Screening of anticancer drugs that could down-regulate the phospho-Akt level and the Akt kinase activity revealed that UCN-01 and Hsp90 inhibitors possessed the ability to interfere Akt pathway. These results strongly suggested that Akt-mediated survival-signaling pathway is a promising and an attractive target for cancer chemotherapy. To identify new molecular targets for developing new anti-cancer drugs, we are now trying to clarify the mechanisms of PDK1/Akt binding partners and their regulation.
(3) Aggrus: a platelet aggregation-inducing factor that is associated with tumor metastasis
Platelet adhesive glycoprotein receptors and their counterparts expressed on tumor cells participate in tumor-induced platelet aggregation, which may be an early step in the development of a metastatic lesion. We have previously characterized the platelet aggregation-inducing sialoglycoprotein (Aggrus) overexpressed in highly metastatic tumors. We recently identified that Aggrus is identical to podoplanin that is known as a lymphatic endothelial cell marker. Expression of Aggrus induced platelet aggregation without requiring plasma components. Using a platelet aggregation-neutralizing monoclonal antibody, we identified the highly conserved platelet aggregation-stimulating domain (PLAG domain) with putative O-glycosylated threonine residues as the critical determinant for exhibiting platelet aggregation-inducing capabilities. The aggrus mRNA expression is found to be frequently upregulated in seminomas and in lung squamous cell carcinomas. These results suggest that Aggrus/podoplanin is a newly identified platelet aggregation-inducing factor that promotes the formation of pulmonary metastasis.
(4) Targeting cancer stem cells for overcoming drug resistance
During the cancer chemotherapy, the "Relapse" makes it difficult to achieve complete cure of cancer. It is thought that present anti-cancer drugs could not kill small population of cancer cells. The cells were called "cancer stem cells". They were known to possess stem cell like properties. Therefore, we are now trying to clarify the properties of the cancer stem cells and to find the new strategies to kill cancer stem cells.
1. Cell-permeable carboxy-terminal p27Kip1 peptide exhibits anti-tumor activity by inhibiting Pim-1 kinase. Daisuke Morishita, Miho Takami, Seiko Yoshikawa, Ryohei Katayama, Shigeo Sato, Mutsuko Kukimoto-Niino, Takashi Umehara, Mikako Shirouzu, Kazuhisa Sekimizu, Shigeyuki Yokoyama and Naoya Fujita.
J. Biol. Chem., 286: 2681-2688, 2011.
2. A transmembrane glycoprotein, gp38, is a novel marker for immature hepatic progenitor cells in fetal mouse livers. Sayuri Konishi, Kentaro Yasuchika, Takamichi Ishii, Ken Fukumitsu, Naoko Kamo, Naoya Fujita, Iwao Ikai, and Shinji Uemoto.
In Vitro Cell. Dev. Biol. Anim., 47: 45-53, 2011.
3. The novel metastasis promoter Merm1/Wbscr22 enhances tumor cell survival in the vasculature by suppressing Zac1/p53-dependent apoptosis. Youya Nakazawa, Hiroyuki Arai, and Naoya Fujita.
Cancer Res., 71: 1146-1155, 2011.
4. Transforming growth factor-β decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells. Shogo Ehata, Erik Johansson, Ryohei Katayama, Sumie Koike, Akira Watanabe, Yukari Hoshino, Yoko Katsuno, Akiyoshi Komuro, Daizo Koinuma, Mitsunobu R. Kano, Masakazu Yashiro, Kosei Hirakawa, Hiroyuki Aburatani, Naoya Fujita, and Kohei Miyazono.
Oncogene, 30: 1693-1705, 2011.
5. AP-1-dependent miR-21 expression contributes to chemoresistance in cancer stem cell-like SP cells. Aya Misawa, Ryohei Katayama, Sumie Koike, Akihiro Tomida, Toshiki Watanabe and Naoya Fujita.
Oncol. Res., 19: 23-33, 2010.
6. Mitotic phosphorylation of Aki1 at Ser208 by cyclin B1-Cdk1 complex. Akito Nakamura, Mikihiko Naito, Hiroyuki Arai, and Naoya Fujita.
Biochem. Biophys. Res. Commun, 393: 872-876, 2010.
7. Modulation of Wnt signaling by the nuclear localization of cellular FLIP-L. Ryohei Katayama, Toshiyasu Ishioka, Shinji Takada, Ritsuko Takada, Naoya Fujita, Takashi Tsuruo, and Mikihiko Naito.
J. Cell Sci., 123: 23-28, 2010.
8. Insulin-stimulated interaction with 14-3-3 promotes cytoplasmic localization of lipin-1 in adipocytes. Miklos Peterfy, Thurl E. Harris, Naoya Fujita, and Karen Reue.
J. Biol. Chem., 285: 3857-3864, 2010.
9. Centrosomal Aki1 and cohesin function in separase-regulated centriole disengagement. Akito Nakamura, Hiroyuki Arai, and Naoya Fujita.
J. Cell Biol., 187: 607-614, 2009.
10. Dofequidar fumarate sensitizes cancer stem–like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export. Ryohei Katayama, Sumie Koike, Shigeo Sato, Yoshikazu Sugimoto, Takashi Tsuruo, and Naoya Fujita.
Cancer Sci., 100: 2060-2068, 2009.
11. Intestinal epithelial cancer cell anoikis resistance: EGFR-mediated sustained activation of Src overrides Fak-dependent signaling to MEK/Erk and/or PI3-K/Akt-1. Marie-Josee Demers, Sonya Thibodeau, Dominique Noel, Naoya Fujita, Takashi Tsuruo, Remy Gauthier, Melina Arguin, and Pierre Vachon.
J. Cell. Biochem., 107: 639-654, 2009.
12. PRMT5, a novel TRAIL receptor-binding protein, inhibits TRAIL-induced apoptosis via NF-κB activation. Hiroshi Tanaka, Yutaka Hoshikawa, Tomoko Oh-hara, Sumie Koike, Mikihiko Naito, Tetsuo Noda, Hiroyuki Arai, Takashi Tsuruo, and Naoya Fujita.
Mol. Cancer Res., 7: 557-569, 2009.
13. TUSC4/NPRL2, a novel PDK1-interacting protein, inhibits PDK1 tyrosine phosphorylation and its downstream signaling. Atsuo Kurata, Ryohei Katayama, Toshiki Watanabe, Takashi Tsuruo, and Naoya Fujita.
Cancer Sci., 99: 1827-1834, 2008.
14. Pim kinases promote cell cycle progression by phosphorylating and down-regulating p27Kip1 at the transcriptional and post-transcriptional levels. Daisuke Morishita, Ryohei Katayama, Kazuhisa Sekimizu, Takashi Tsuruo, and Naoya Fujita.
Cancer Res., 68: 5076-5085, 2008.
15. Tetraspanin family member CD9 inhibits Aggrus/podoplanin-induced platelet aggregation and suppresses pulmonary metastasis. Youya Nakazawa, Shigeo Sato, Mikihiko Naito, Yukinari Kato, Kazuhiko Mishima, Hiroyuki Arai, Takashi Tsuruo, and Naoya Fujita.
Blood, 112: 1730-1739, 2008.
16. Involvement of the lysophosphatidic acid-generating enzyme autotaxin in lymphocyte-endothelial cell interactions. Tae Nakasaki, Toshiyuki Tanaka, Shinichi Okudaira, Michi Hirosawa, Eiji Umemoto, Kazuhiro Otani, Soojung Jin, Zhonbin Bai, Haruko Hayasaka, Yoshinori Fukui, Katsuyuki Aozasa, Naoya Fujita, Takashi Tsuruo, Keiichi Ozono, Junken Aoki and Masayuki Miyasaka.
Am. J. Pathol., 173: 1566-1576, 2008.
17. Freud-1/Aki1, a novel PDK1-interacting protein, functions as a scaffold to activate the PDK1/Akt pathway in epidermal growth factor signaling. Akito Nakamura, Mikihiko Naito, Takashi Tsuruo, and Naoya Fujita.
Mol. Cell. Biol., 28: 5996-6009, 2008.
18. β1 integrin/Fak/Src signaling in intestinal epithelial crypt cell survival: integration of complex regulatory mechanisms. Veronique Bouchard, Charlene Harnois, Marie-Josee Demers, Sonya Thibodeau, Vincent Laquerre, Remy Gauthier, Anne Vezina, Dominique Noel, Naoya Fujita, Takashi Tsuruo, Melina Arguin, Pierre H. Vachon.
Apoptosis, 13: 531-542, 2008.
19. FOXO transcription factor-dependent p15INK4b and p19INK4d expression. Kazuhiro Katayama, Akito Nakamura, Yoshikazu Sugimoto, Takashi Tsuruo, and Naoya Fujita.
Oncogene, 27: 1677-1686, 2008.
20. Platelet aggregation in the formation of tumor metastasis (Review). Takashi Tsuruo and Naoya Fujita
Proc. Jpn. Acad., Ser. B, 84: 189-198, 2008.
21. The platelet aggregation-inducing factor Aggrus/podoplanin promotes pulmonary metastasis. Akiko Kunita, Takeshi G. Kashima, Yasuyuki Morishita, Masashi Fukayama, Yukinari Kato, Takashi Tsuruo, and Naoya Fujita.
Am. J. Pathol., 170: 1337-1347, 2007.
22. Two populations of Thy1-positive mesenchymal cells regulate the in vitro maturation of hepatic progenitor cells. Naoko Kamo, Kentaro Yasuchika, Hideaki Fujii, Toshitaka Hoppo, Takafumi Machimoto, Takamichi Ishii, Naoya Fujita, Takashi Tsuruo, Jun K. Yamashita, Hajime Kubo, and Iwao Ikai.
Am. J. Physiol. Gastrointest. Liver Physiol., 292: G526-G534, 2007.
23. Casein kinase 2-interacting protein-1, a novel Akt Pleckstrin homology domain-interacting protein, down-regulates PI3K/Akt signaling and suppresses tumor growth in vivo. Emi Tokuda, Naoya Fujita, Tomoko Oh-hara, Shigeo Sato, Atsuo Kurata, Ryohei Katayama, Toshiki Itoh, Tadaomi Takenawa, Kohei Miyazono, and Takashi Tsuruo.
Cancer Res., 67: 9666-9676, 2007.
24. p27Kip1 localization depends on the tumor suppressor protein tuberin. Margit Rosner, Angelika Freilinger, Michaela Hanneder, Naoya Fujita, Gert Lubec, Takashi Tsuruo, and Markus Hengstschlager.
Hum. Mol. Genet., 16: 1541-1556, 2007.
25. Fak/Src signaling in human intestinal epithelial cell survival and anoikis: Differentiation state-specific uncoupling with the PI3-K/Akt-1 and MEK/Erk pathways. Veronique Bouchard, Marie-Josee Demers, Sonya Thibodeau, Vincent Laquerre, Naoya Fujita, Takashi Tsuruo, Jean-Francois Beaulieu, Remy Gauthier, Anne Vezina, Lisabeth Villeneuve, and Pierre H. Vachon.
J. Cell. Physiol., 212: 717-728, 2007.
26. Differentiation of lymphatic endothelial cells from Embryonic Stem cells on OP9 stromal cells. Tomoya Kono, Hajime Kubo, Chikashi Shimazu, Yoshihide Ueda, Meiko Takahashi, Kentoku Yanagi, Naoya Fujita, Takashi Tsuruo, Hiromi Wada and Jun K. Yamashita.
Arterioscler Thromb. Vasc. Biol., 26: 2070-2076, 2006.
27. Podoplanin expression in primary central nervous system germ cell tumors: A useful histological marker for the diagnosis of germinoma. Kazuhiko Mishima, Yukinari Kato, Mika K. Kaneko, Youya Nakazawa, Akiko Kunita, Naoya Fujita, Takashi Tsuruo, Ryo Nishikawa, Takanori Hirose and Masao Matsutani.
Acta Neuropathol., 111: 563-568, 2006.
28. Binding and phosphorylation of Par-4 by Akt is essentilal for cancer cell survival. Anindya Goswami, Ravshan Burikhanov, Aurelie de Thonel, Naoya Fujita, Mamta Goswami, Yanming Zhao, John E. Eriksson, Takashi Tsuruo, and Vivek M. Rangnekar.
Mol. Cell, 20: 33-44, 2005.
29. Akt/protein kinase B-dependent phosphorylation and inactivation of WEE1Hu promotes cell cycle progression at G2/M transition. Kazuhiro Katayama, Naoya Fujita, and Takashi Tsuruo.
Mol. Cell. Biol., 25: 5725-5737, 2005.
30. 3-Phosphoinositide-dependent protein kinase-1-mediated IκB kinase β (IKKB) phosphorylation activates NF-κB signaling. Hiroshi Tanaka, Naoya Fujita, and Takashi Tsuruo.
J. Biol. Chem., 280: 40965-40973, 2005.
31. Involvement of mitochondrial aggregation in arsenic trioxide (As2O3)-induced apoptosis in human glioblastoma cells. Naomi Haga, Naoya Fujita, and Takashi Tsuruo.
Cancer Sci., 96: 825-833, 2005.
32. Stabilization of integrin-linked kinase by binding to Hsp90. Yumiko Aoyagi, Naoya Fujita, and Takashi Tsuruo.
Biochem. Biophys. Res. Commun., 331: 1061- 1068, 2005.
33. CXCL13 is an arrest chemokine for B cells in high endothelial venules. Naotoshi Kanemitsu, Yukihiko Ebisuno, Toshiyuki Tanaka, Kazuhiro Otani, Haruko Hayasaka, Tsuneyasu Kaisho, Shizuo Akira, Koko Katagiri, Tatsuo Kinashi, Naoya Fujita, Takashi Tsuruo, and Masayuki Miyasaka.
Blood, 106: 2613-2618, 2005.
34. Enhanced expression of Aggrus (T1α/podoplanin), a platelet aggregation-inducing factor in lung squamous cell carcinoma. Yukinari Kato, Mika Kaneko, Makoto Sata, Naoya Fujita, Takashi Tsuruo, and Motoki Osawa.
Tumour Biol., 26: 195-200, 2005.
35. Human intestinal epithelial cell survival and anoikis: Differentiation state-distinct regulation and roles of protein kinase B/Akt isoforms. Geneviee Dufour, Marie-Josee Demers, David Gagne, Anders Bondo Dydensborg, Inga C. Teller, Veronique Bouchard, Isabelle Degongre, Jean-Francois Beaulieu, Jin Q. Cheng, Naoya Fujita, Takashi Tsuruo, Karine Vallee, and Pierre H. Vachon.
J. Biol. Chem., 279: 44113-44122, 2004.
36. Functional sialylated O-glycan to platelet aggregation on Aggrus (T1α/podoplanin) molecules expressed in Chinese hamster ovary cells. Mika Kaneko, Yukinari Kato, Akiko Kunita, Naoya Fujita, Takashi Tsuruo, and Motoki Osawa. J. Biol. Chem., 279: 38838-38843, 2004.
37. Involvement of 3-phosphoinositide-dependent protein kinase-1 in the MEK/MAPK signal transduction pathway. Saori Sato, Naoya Fujita, and Takashi Tsuruo.
J. Biol. Chem., 279: 33759-33767, 2004.
38. Aggrus: a diagnostic marker that distinguishes seminoma from embryonal carcinoma in testicular germ cell tumors. Yukinari Kato, Isoji Sasagawa, Mika Kaneko, Motoki Osawa, Naoya Fujita, and Takashi Tsuruo.
Oncogene, 23: 8552-8556, 2004.
39. Reconstitution of caspase-3 confers low glucose-enhanced tumor necrosis factor-related apoptosis-inducing ligand cytotoxicity and Akt cleavage. Yong J. Lee, Christopher J. Froelich, Naoya Fujita, Takashi Tsuruo, and Jin H. Kim.
Clin. Cancer Res., 10: 1894-1900, 2004.
40. Human intestinal epithelial crypt cell survival and death: Complex modulations of Bcl-2 homologs by Fak, PI3-K/Akt-1, MEK/Erk, and p38 signaling pathways. Charlene Harnois, Marie-Josee Demers, Veronique Bouchard, Karine Vallee, David Gagne, Naoya Fujita, Takashi Tsuruo, Anne Vezina, Jean-Francois Beaulieu, Andre Cote, and Pierre H. Vachon.
J. Cell. Physiol., 198: 209-222, 2004.
41. Molecular identification of Aggrus/T1α as a platelet aggregation-inducing factor expressed in colorectal tumors. Yukinari Kato, Naoya Fujita, Akiko Kunita, Shigeo Sato, Mika Kaneko, Motoki Osawa, and Takashi Tsuruo.
J. Biol. Chem., 278: 51599-51605, 2003.
42. Phosphorylation of p27Kip1 at threonine 198 by p90 ribosomal protein S6 kinases promotes its binding to 14-3-3 and cytoplasmic localization. Naoya Fujita, Saori Sato, and Takashi Tsuruo.
J. Biol. Chem., 278: 49254-49260, 2003.
43. Rap1 translates chemokine signals to integrin activation, cell polarization, and motility across vascular endothelium under flow. Mika Shimonaka, Koko Katagiri, Toshinori Nakayama, Naoya Fujita, Takashi Tsuruo, Osamu Yoshie, and Tatsuo Kinashi.
J. Cell Biol., 161: 417-427, 2003.
44. Mitochondrial aggregation precedes cytochrome c release from mitochondria during apoptosis. Naomi Haga, Naoya Fujita, and Takashi Tsuruo.
Oncogene, 22: 5579-5585, 2003.
45. Involvement of FKHR-dependent TRADD expression in chemotherapeutic drug-induced apoptosis. Susumu Rokudai, Naoya Fujita, Osamu Kitahara, Yusuke Nakamura, and Takashi Tsuruo.
Mol. Cell. Biol., 22: 8695-8708, 2002.
46. Critical involvement of the phosphatidylinositol 3-kinase/Akt pathway in anchorage-independent growth and hematogenous intrahepatic metastasis of liver cancer. Kazuaki Nakanishi, Michiie Sakamoto, Jun Yasuda, Masaaki Takamura, Naoya Fujita, Takashi Tsuruo, Satoru Toda, and Setsuo Hirohashi.
Cancer Res., 62: 2971-2975, 2002.
47. Ceramide and reactive oxygen species generated by H2O2 induce caspase-3-independent degradation of Akt/protein kinase B. Daniel Martin, Marta Salinas, Naoya Fujita, Takashi Tsuruo, and Antonio Cuadrado.
J. Biol. Chem., 277: 42943-42952, 2002.
48. Regulation of kinase activity of 3-phosphoinositide-dependent kinase-1 by binding to 14-3-3. Saori Sato, Naoya Fujita, and Takashi Tsuruo.
J. Biol. Chem., 277: 39360-39367, 2002.
49. Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization. Naoya Fujita, Saori Sato, Kazuhiro Katayama, and Takashi Tsuruo.
J. Biol. Chem., 277, 28706-28713, 2002.
50. Transforming growth factor-β induces expression of receptor activator of NF-kappaB ligand in vascular endothelial cells derived from bone. Atsushi Ishida, Naoya Fujita, Riko Kitazawa, and Takashi Tsuruo.
J. Biol. Chem., 277: 26217-26224, 2002.
51. Involvement of Hsp90 in signaling and stability of 3-phosphoinositide-dependent kinase-1. Naoya Fujita, Saori Sato, Atsushi Ishida, and Takashi Tsuruo.
J. Biol. Chem., 277: 10346-10353, 2002.
52. Domain mapping studies reveal that the M domain of hsp90 serves as a molecular scaffold to regulate Akt-dependent phosphorylation of endothelial nitric oxide synthase and NO release. Jason Fontana, David Fulton, Yan Chen, Todd A. Fairchild, Timothy J. McCabe, Naoya Fujita, Takashi Tsuruo, and William C. Sessa.
Circ. Res., 90: 866-873, 2002.
53. Clonal endothelial cells produce humoral factors that inhibit osteoclast-like cell formation in vitro. Noriko Chikatsu, Yasuhiro Takeuchi, Seiji Fukumoto, Kazuki Yano, Naoya Fujita, Takashi Tsuruo, and Toshiro Fujita.
Endocr. J., 49: 439-447, 2002.
54. Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). Saori Sato, Naoya Fujita, and Takashi Tsuruo.
Oncogene, 21: 1727-1738, 2002.
55. Topotecan inhibits VEGF- and bFGF-induced vascular endothelial cell migration via downregulation of PI3K-Akt signaling pathway. Ayako Nakashio, Naoya Fujita, and Takashi Tsuruo.
Int. J. Cancer, 98: 36-41, 2002.
56. The cleavage of Akt/PKB by death receptor signaling is an important event in detachment-induced apoptosis. Robin E. Bachelder, Melissa A. Wendt, Naoya Fujita, Takashi Tsuruo, and Arthur M. Mercurio.
J. Biol. Chem., 276: 34702-34707, 2001.
57. Prevention of phosphatidylinositol 3'-kinase-Akt survival signaling pathway during topotecan-induced apoptosis. Ayako Nakashio, Naoya Fujita, Susumu Rokudai, Saori Sato, and Takashi Tsuruo.
Cancer Res., 60: 5303-5309, 2000.
58. Cleavage and inactivation of anti-apoptotic Akt/PKB by caspases during apoptosis. Susumu Rokudai, Naoya Fujita, Yuichi Hashimoto, and Takashi Tsuruo.
J. Cell. Physiol., 182: 290-296, 2000.
59. Modulation of Akt kinase activity by binding to Hsp90. Saori Sato, Naoya Fujita, and Takashi Tsuruo.
Proc. Natl. Acad. Sci. USA, 97: 10832-10837, 2000.
American Association for Cancer Research
The Japanese Cancer Association
The Japanese Association for Metastasis Research
Chemotherapy Research and Practice
Although cancer treatments have gradually improved during past decades, we are still facing problems to surmount in prevention and therapy of cancers. Recent advances in molecular-based understanding of cell proliferation have provided the rationale for the molecular-targeted therapy to control cancer. The aim of our research is to identify possible targets, to clarify the function of molecular targets, and ultimately to develop an effective molecular-targeted therapy of cancer. For this purpose, we are investigating the molecular mechanisms of anti-cancer drug resistance, apoptosis resistance, tumor metastasis and cancer stem cells. |
|Messages to Students|
I hope you will join us to develop new drugs to achieve complete cure of cancer.|