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Franklin G. Berger

Director, Center for Colon Cancer Research
Department of Biology
University of South Carolina

Office: PSC 614
Phone Number: Office: 803-777-1171; Lab: 803-777-7216; Office: 803-777-1231
Email: fgberger@mailbox.sc.edu
Website: Berger Lab/ Center for Colon Cancer Research
Vitae: Download PDF

Background: Colorectal cancer is the fourth-highest cancer in terms of incidence, and second-leading cause of cancer death.  In the US, over 140,000 new cases of colorectal cancer are diagnosed each year, and nearly 50,000 patients die from the disease.  Like most cancers, less-than-optimal efficacy of anti-neoplastic agents is a major barrier to the successful treatment of advanced colorectal cancer.  The high genetic plasticity of neoplastic cells generally leads to rapid emergence of resistance to chemotherapeutic agents, reducing therapeutic effectiveness.  For several years, we have been examining an important class of chemotherapeutic agents that target the pyrimidine biosynthetic enzyme thymidylate synthase (TS).  TS catalyzes the  reductive methylation of dUMP to form dTMP, which is indispensible for DNA synthesis during cell proliferation and DNA repair. Treatment of cells with fluoropyrimidine analogs (e.g., 5-fluorouracil and 5-fluoro-2'- deoxyuridine), as well as antifolates (e.g., tomudex, AG337, and BW1843), results in the generation of metabolites that inhibit TS, causing depletion of thymidylate pools, cessation of cell growth, and eventually, cell death. Thus, TS inhibitors have been useful in the treatment of a variety of neoplasms.  However, a large fraction of patients do not respond to these drugs; furthermore, those that do respond typically develop resistance.

Oxidative stress and cell death in response to TS inhibition:  We have recently shown that apoptosis in response to TS inhibitors is due to oxidative stress brought on by increased concentrations of reactive oxygen species (ROS) resulting from activation of the enzyme NADPH oxidase (NOX).  NOX, which occurs as a membrane-bound multi-subunit complex, catalyzes transfer of an electron from NADPH to molecular oxygen to form superoxide, which is essential for maximal response to TS inhibitors.  The mechanism of NOX activation by TS inhibitors is not completely understood, but likely involves induction of expression of the NCF2 gene, which encode the NOX regulatory subunit p67phox .

Role of the anti-oxidant genes in response to TS inhibitors: Using cDNA microarrays, we have recently determined that cells mount a protective response to TS inhibitors, involving activation of genes involved in amelioration of oxidative and electrophilic stress.  Many of these genes are regulated by transcription factor Nrf2, which is well-known to attenuate the concentration and impact of ROS.  We have postulated that the expression and activation of Nrf2 is a constraining factor in cell death following TS inhibition.  Indeed, we have observed that down-regulation of Nrf2 by siRNAs sensitizes cells to the cytotoxic effects of TS inhibitors.  Our current efforts, summarized in the figure below, are focused on understanding the role of Nrf2 in response toTS-directed drugs, and using the information gained to increase the efficacy of this important class of therpaeutic agents.


REFERENCE

Ozer, U., Barbour, K.W., Clinton, S.A., and Berger, F.G. 2015.  Oxidative stress and response to thymidylate synthase-targeted antimetabolites.  Molecular Pharmacology 88: 970-981.