Biochemistry & Cancer Biology

Manohar Ratnam, Ph.D.

Manohar Ratnam, Ph.D.
Professor of Biochemistry & Cancer Biology
manohar.ratnam@utoledo.edu 

RESEARCH INTERESTS:

The specific disease focus of my current research includes: (i) improvement in breast cancer adjuvant therapy; (ii) early detection of breast and ovarian cancer; (iii) new approaches to treating proliferative disorders of the prostate; and (iv) molecular approaches to targeted drug delivery in acute myelogenous leukemia.

In recent years, we have discovered non-classical mechanisms of transcriptional regulation of genes by the nuclear receptor superfamily, including various steroid receptors and the retinoic acid receptor. The new findings have found broad implications in global gene regulation mechanisms and in the mechanism-based treatment of different cancers including breast cancer, ovarian cancer, prostate cancer and myelogenous leukemias. Our recent studies have shed new light on mechanisms underlying the progression of breast and prostate cancers and have identified possible ways of improving upon current therapies. In the foreseeable future, my laboratory’s broad research interests will continue to expand into the molecular endocrinology of nuclear receptors while continuing to pursue our previous advanced studies of folate receptor-targeted therapeutics (see below).

In previous years, my laboratory pioneered the discovery and characterization of the folate receptor gene family and helped to establish the potential utility of FR isoforms in the targeted therapy of various types of cancer as well as inflammatory diseases. Those studies involved detailed investigations of structure-function and gene regulation of FRs. Our contributions to the field have supported more recent advances in the clinical arena where an explosion of various types of folate drug conjugates, immunotherapies, novel antifolates and nanoparticles are showing great promise as therapeutics for cancer and inflammatory diseases. We are now at a stage in which our additional ideas on the potential utility of FRs as serum markers for the early detection of ovarian, endometrial and breast cancers must be investigated in clinical studies.

Member of the mentoring faculty for the Biomedical Sciences Graduate Program (Cancer Biology track and Cardiovacular and Metabolic Diseases track).

EDUCATION:

Ph.D. 1983 Indian Institute of Science, Bangalore, India (Biochemistry)
M.Sc. 1978 University of Mysore, Mysore, India (Biosciences) First Rank (First in University)
B.Sc. 1976 University of Mysore, Mysore, India (Chemistry, Botany and Zoology)

ACADEMIC APPOINTMENTS:

2005 - present Scientific Director, University Cancer Center
2005 - present Harold and Helen McMaster Chair in Biochemistry and Molecular Biology
1998 - present Professor, Biochemistry and Cancer Biology, University of Toledo College of Medicine 
1994 - 1998 Associate Professor, Biochemistry and Molecular Biology Medical University of Ohio
1993 - 1997 Consultant Eli Lilly and Co., Indianapolis, IN.
1990 - 1993 Assistant Professor, Biochemistry and Molecular Biology Medical University of Ohio
1990 Affiliate Assistant Professor, Dept. of Pathobiology, University of Washington, Seattle, WA.
1989 - 1990 Senior Scientist Oncogene, Bristol-Myers Squibb Co.
1986 - 1989 Instructor, Medical University of Ohio
1985 - 1986 Research Associate, Biochemistry Medical College of Ohio
1983 - 1985 Postdoctoral Fellow, Receptor Biology Laboratory Salk Institute, San Diego, CA
1980 - 1983 Editorial Assistant Journal of Bioscience

PROFESSIONAL AFFILIATIONS & ACTIVITIES:

Regular Member of NIH Study Section, Basic Mechanisms of Cancer Therapeutics (BMCT) - March 2007-February 2011
Regular Member of NIH Study Section, Experimental Therapeutics - July 1997-June 2001
Ad hoc Reviewer for NIH Study Section BMCT - November 2005, June 2006, October 2006, January 2007
Ad hoc Reviewer for NIH Study Section ET-1 - February 1996, October 1996, February 1997, June 2003
NIH Special Emphasis Panels - May 1999, April 2000, August 2000, December 2000 (Chair), December 2003, June 2004, December 2004, August 2005
External Reviewer for Ohio University College of Osteopathic Medicine's competitive grant program - November 2006
External Grant Reviewer for Ohio Cancer Research Associates - April 2001
Member of Review Committee for American Cancer Society (Ohio Chapter) - 1995-1998
Grant Reviewer for Veterans Administration Office of External Reviews - September 2001
External Grant Reviewer for The Hospital for Sick Children Foundation, Toronto, Ontario, Canada - 1998-present
Grant Reviewer for American Chemical Society Petroleum Research Fund - 2001
Grant Reviewer for Biotechnology and Biological Sciences Research Council, U.K. - 2002

Journal Peer Review:

Nature Medicine, Molecular Biology of the Cell, Journal of Clinical Investigation, Blood, Cancer Research, Clinical Cancer Research, The Journal of Biological Chemistry, Journal of Molecular Biology, Biochemistry, Nucleic Acids Research, American Journal of Physiology, Biochemical Pharmacology, Gynecologic Oncology, Cell Proliferation, Biochimica et Biophysica Acta, Journal of Nutrition, Archives of Biochemistry and Biophysics, Gene, Developmental Dynamics, International Journal of Cancer, Biotechnology & Applied Biochemistry

REPRESENTATIVE PUBLICATIONS:

Gonit, M., Zhang, J., Salazar, M., Cui, H., Shatnawi, A., Trumbly, R., and Ratnam, M. (2011) Hormone depletion-insensitivity of prostate cancer cells is supported by the AR without binding to classical response elements.  Mol. Endocrinol.  25:621-634.

Salazar, M.D., Ratnam, M., Patki, M., Kisovic, I., Trumbly, R., Iman, M., and Ratnam, M. (2011) During hormone depletion or tamoxifen treatment of breast cancer cells the estrogen receptor apoprotein supports cell cycling through the retinoic acid receptor α1 apoprotein.  Breast Cancer Res. 13:R18. 

Sivakumaran, S., Zhang, J., Kelley, K.M., Gonit, M., Hao, H., and Ratnam, M. (2010) Androgen activation of the folate receptor α gene through partial tethering of the androgen receptor by C/EBPα.  J. Steroid Biochem. Mol. Biol. 122:333-340.

Zhang, J., Gonit, M., Salazar, MD, Shatnawi, A., Shemshedini, L., Trumbly, R., and Ratnam, M. (2009)  C/EBPalpha redirects androgen receptor signaling through a unique bimodal interaction. Oncogene  29:723-738.

Elnakat, H., Gonit, M., d'Alincourt Salazar, M., Zhang, J., Basrur V., Gunning, W., Kamen, B., and Ratnam, M. (2009) Regulation of folate receptor internalization by protein kinase C alpha.  Biochemistry 48:8249-8260.

van der Heijden, J.W., Oerlemans, R., Dijkmans, B.A.C., Qi, H., van der Laken, C.J., Lems, W.F., Jackman, A.L., Kraan, M.C., Tak, P.P., Ratnam, M., and Jansen G. (2009) Folate receptor beta as a potential delivery route for novel folate antagonists to macrophages in the synovial tissue of rheumatoid arthritis patients.  Arthritis and Rheumatism 60:12-21.

Zhang, J., Wilkinson, J.E., Gonit, M., Keck, R., Selman. S. and Ratnam, M. (2008) Expression and sub-cellular localization of the CCAAT/enhancer binding protein alpha in relation to postnatal development and malignancy of the prostate. Prostate 68:1206-1214.

Blaser, B., Gonit, M., Qi, H., Shatnawi, A., Guimond, M., Lee, R.J., and Ratnam, M. (2007) Induction of folate receptor type beta in a bone marrow engraftment model of acute myelogenous leukemia.  Leukemia 21: 2233-2235.

Hao, H., d'Alincourt-Salazar, M., Kelley, K.M.M., Shatnawi, A., Mukherjee, S., Shah, Y.M. and Ratnam, M. (2007) Estrogen-induced and TAFII30-mediated gene repression by direct recruitment of the estrogen receptor and co-repressors to the core promoter and its reversal by tamoxifen.  Oncogene 13:7872-7884.

Lu, Y., Wu., J., Wu, J., Gonit, M., Yang, X., Lee, A., Xiang, G., Li, H., Liu, S., Marcucci, G., Ratnam, M.*, and Lee, R.* (2007) Role of formulation composition in folate receptor-targeted liposomal doxorubicin delivery to acute myelogenous leukemia cells.  Mol. Pharm. 4:707-712.  (*equal contributors)

Shatnawi, A., Tran, T. and Ratnam, M. (2007) R5020 and RU486 act as progesterone receptor agonists to enhance Sp1/Sp4-dependent gene transcription by an indirect mechanism. Mol. Endocrinol. 21:635-650.

Salazar, M.D., and Ratnam, M. (2007) The folate receptor: what does it promise in tissue-targeted therapeutics?  Cancer Met. Rev. 26:141-152.

Elnakat, H. and Ratnam, M. (2006) Role of folate receptor genes in reproduction and related cancers.  Frontiers in Bioscience 11:506-519.

Qi, H. and Ratnam, M. (2006) Synergistic induction of folate receptor beta by all-trans retinoic acid and histone deacetylase inhibitors in acute myelogenous leukemia cells: mechanism and utility in enhancing selective growth inhibition by antifolates.  Cancer Res. 66:5875-5882.

Tran, T., Shatnawi, A., Zheng, X., Kelley, K.K.M., and Ratnam, M. (2005) Enhancement of folate receptor alpha expression in tumor cells through the glucocorticoid receptor: a promising means to improved tumor detection and targeting. Cancer Res. 65:4431-4441.

Elnakat, H. and Ratnam. M. (2004) Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy.  Adv. Drug Delivery Rev. 56:1067-1084.

Hao, H., Qi, H. and Ratnam, M. (2003) Modulation of the folate receptor type beta gene by coordinate actions of retinoic acid receptors at activator Sp1/ets and repressor AP-1 sites. Blood 101:4551-4560.

Kelley, K.M., Rowan, B.G. and Ratnam, M. (2003) Modulation of the folate receptor alpha gene by the estrogen receptor: mechanism and implications in tumor targeting. Cancer Res. 63:2820-2828.

Kelley, K.M., Wang, H. and Ratnam, M. (2003) Dual regulation of ets-activated gene expression by SP1. Gene 27:87-97.

Ratnam, M., Hao, H., Zheng, X., Wang, H., Qi, H., Lee, R. and Pan, X. (2003) Receptor induction and targeted drug delivery: a new antileukaemia strategy.  Expert Opin. Biol. Ther. 3: 563-574.

Zheng, X., Yan, W., Kelley, K., Dorn, T. and Ratnam, M. (2003) mRNA instability in the nucleus due to a novel open reading frame element is a major determinant of the narrow tissue specificity of folate receptor alpha. Mol. Cell. Biol. 23:2202-2212.

Pan, X.Q., Zheng, X., Shi, G., Wang, H., Ratnam, M. and Lee, R.J. (Equal Contribution from the Ratnam and Lee Labs) (2002) Strategy for the treatment of acute myelogenous leukemia based on folate receptor beta-targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid. Blood 100:594-602.

Wang, H., Zheng, X., Behm, F.-G. and Ratnam, M. (2000) Differentiation-independent retinoid induction of folate receptor type beta, a potential tumor target in myeloid leukemia.  Blood 96:3529-3536.



Last Updated: 6/26/15