Dr. Fuyukiko Tamanoi's research focuses on signal transduction involving the Ras-superfamily G-proteins, protein farnesylation and anti-cancer drugs. The Ras-superfamily G-proteins play critical roles in cell growth and differentiation. Tamanoi and his colleagues have investigated the function and cellular localization of Ras that is mutated in a wide range of human cancer. Recently, they have focused their attention on a novel family of the Ras-superfamily G-proteins called Rheb. Rheb possesses a unique structural feature and is conserved in a number of organisms. Genetic studies using yeast and Drosophila established that Rheb plays critical roles in both cell growth and cell cycle progression at the G1/S boundary. This function of Rheb is mediated by its ability to activate the mTOR/S6K signaling pathway. Transient transfection of Rheb leads to the activation of S6K in mammalian cells. Interestingly, Rheb is found to be a target of TSC2. Mutations of TSC2 are responsible for tuberous sclerosis, a genetic disease associated with benign tumors and mental retardation.
Tamanoi's laboratory also is developing anti-cancer drugs against Ras. One approach that has been taken is to block Ras function by inhibiting farnesylation of Ras that is critical for its membrane association. Farnesylation is catalyzed by protein farnesyltransferase (FTase), a highly conserved heterodimeric enzyme. Inhibitors of FTase (FTIs) have been developed. These small molecular weight compounds exhibit remarkable ability to block the growth of tumors or even regress tumors in animal model systems, and are currently evaluated in clinical trials. The researchers found that FTIs cause inhibition of anchorage-independent growth, morphophological changes, induction of apoptosis and changes in cell cycle progression. Mechanism of action of FTIs is being investigated. Another approach recently explored is to develop a novel Ras inhibitor that blocks activation of Raf kinase by Ras. The activation of Raf causes activation of MEK and ERK. The researchers have identified compounds, called MCP compounds, that block Raf kinase activity, inhibit anchorage-independent growth and cause accumulation of G1 phase cells. Mechanism of action of these compounds on human cancer cell lines is being investigated.
Another research interest of Tamanoi's lab is utilization of silica nanoparticles for controllable drug delivery system for cancer therapy. One of the major problems in clinical use of anti-cancer drugs is that many of them are hydrophobic, which poses a critical obstacle for cancer therapy. Tamanoi's team uses mesoporous silica nanoparticles prepared in the presence of surfactants. These nanoparticles have the diameter of approximately 130 nm and contain thousands of pores whose diameter is about 3 nm. Tamanoi and his researchers incorporate different hydrophobic anticancer drugs, such as camptothecin (CPT) and taxol, into the pores of the mesoporous silica nanoparticles and deliver the drug to a variety of human cancer cells. This causes cell death. Tamanoi's lab is also exploring ways to use molecular valves to carry out controlled release of anti-cancer drugs with the mesoporous silica nanoparticles. One of Tamanoi's approaches is to use molecules that change conformation by light exposure to accomplish controlled delivery. Targeting to cancer by attaching ligands specific to cancer cells is currently being investigated.
Selected Cancer-Related Publications:
Lu J, Liong M, Li Z, Zink JI, Tamanoi F. Biocompatibility, biodistribution, and drug-delivery efficiency of mesoporous silica nanoparticles for cancer therapy in animals. Small. 2010 Aug 16;6(16):1794-805.
Jiang H, Song C, Chen CC, Xu R, Raines KS, Fahimian BP, Lu CH, Lee TK, Nakashima A, Urano J, Ishikawa T, Tamanoi F, Miao J. Quantitative 3D imaging of whole, unstained cells by using X-ray diffraction microscopy. Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11234-9. Epub 2010 Jun 4.
Sato T, Nakashima A, Guo L, Coffman K, Tamanoi F. Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer. Oncogene. 2010 May 6;29(18):2746-52. Epub 2010 Mar 1.
Nakashima A, Sato T, Tamanoi F. Fission yeast TORC1 regulates phosphorylation of ribosomal S6 proteins in response to nutrients and its activity is inhibited by rapamycin. J Cell Sci. 2010 Mar 1;123(Pt 5):777-86. Epub 2010 Feb 9.
Sato T, Nakashima A, Tamanoi F. [Rheb-mTOR signaling pathway involved in tumor formation] Tanpakushitsu Kakusan Koso. 2010 Jan;55(1):11-7. [Article in Japanese]