Masahiro Higuchi, Ph.D.  

Assistant Professor

Ph.D., University of Tokyo, Tokyo, Japan

Roles of mitochondria and mitochondrial DNA in apoptosis and cancer progression

Mitochondria are now considered a key organelle regulating cell death, growth and differentiation. We showed that depletion of mitochondrial DNA (mtDNA) reduced apoptosis induced by specific mediators. We also showed that mtDNA regulate prostate cancer hormone-dependence and aggressive phenotype. We also observed that cells with reduced mtDNA content increases associated with cancer development possibly induced by high frequency of mutation to mtDNA in cancer. We observed constitutive activation of NF-kB, ERK, AKT and JNK which are considered as a cause for cancer progression, ageing, diabetes and neurodegenerative diseases. We are further investigating the detailed mechanisms involved how mitochondrial changes induce those abnormal signaling. We also investigate whether and how we will reverse aggressive phenotype of prostate cancer cells by regulating mitochondrial function.

Selected Publications

Suzuki, S., Naito, A., Asano, T., Evans, T., SAG., R., and M, Higuchi. (2008). Constitutive Activation of AKT Pathway Inhibits TNF-induced Apoptosis in Mitochondrial DNA-Deficient human myelogenous leukemia ML-1a. Cancer letter 268:31-37.

Naito, A., Mizumachi, T., Wang, M., Xie, C.H., Evans, T.T., Kelly, T., and Higuchi, M. (2008). Progressive tumor features accompany epithelial-mesenchymal transition induced in mitochondrial DNA depleted cells. Cancer Science 99:1584-1588.

Naito, A., Carcel-Trullols, J., Xie, C.H., Evans, T.T., Mizumachi, T., and Higuchi, M. (2008). Induction of acquired resistance to antiestrogen by reversible mitochondrial DNA depletion in breast cancer cell line. International Journal of Cancer 122:1506-1511.

Mizumachi, T., Suzuki, S., Naito, A., Carcel-Trullols, J., Evans, T.T., Spring, P.M., Oridate, N., Furuta, Y., Fukuda, S., and Higuchi, M. (2008). Increased mitochondrial DNA induces acquired docetaxel resistance in head and neck cancer cells. Oncogene 27:831-838.

Mizumachi, T., Muskhelishvili, L., Naito, A., Furusawa, J., Fan, C.Y., Siegel, E.R., Kadlubar, F.F., Kumar, U., and Higuchi, M. (2008). Increased distributional variance of mitochondrial DNA content associated with prostate cancer cells as compared with normal prostate cells. Prostate 68:408-417.

Xie, C.H., Naito, A., Mizumachi, T., Evans, T.T., Douglas, M.G., Cooney, C.A., Fan, C.Y., and Higuchi, M. (2007). Mitochondrial regulation of cancer associated nuclear DNA methylation. Biochemical & Biophysical Research Communications 364:656-661.

Higuchi, M. Regulation of mitochondrial DNA content and cancer. Mitochondrion in press (2007)

Higuchi, M., Kudo T., Evans T., Sasaki R., Wada T., Shirakawa T., Sawyer JR., and Gotoh, A. Mitochondrial DNA Determines Androgen Sensitivity in Prostate Cancer Cell Lines. Oncogene 25 1437-1445 (2006)

Higuchi, M., Aggarwal, B. B. and Yeh, E. T. H.: Activation of CPP32-like protease in TNF-induced apoptosis is dependent on mitochondrial function. J. Clin. Invest.  99, 1751-1758 (1997)

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Department of Biochemistry and Molecular Biology
University of Arkansas for Medical Sciences
4301 W. Markham St., Slot 516
Little Rock, AR 72205