Leroy F. Liu

Current Institution
Taipei Medical University
Center for Cancer Research

Scholar: 1981

Awarded Institution
The Johns Hopkins University


Research Interests

Professor Liu's laboratory is interested in cancer biology and cancer pharmacology. Currently, three areas of research are being actively pursued:

Topoisomerase I as a new molecular target for anticancer drugs-Our studies have established that topoisomerase I is the molecular target for camptothecin, a plant alkaloid, known to exhibit antitumor activity against many solid tumors. We have shown that camptothecin inhibits TOP1 by stabilizing a covalent reaction intermediate termed the cleavable complex which ultimately causes tumor cell death. Currently, we are investigating the molecular basis for hTOP1 inhibition by camptothecin and the molecular mechanism of tumor cell death.

Repair of topoisomerase I-mediated DNA damage-Topoisomerase-mediated DNA damage, which represents a unique form of DNA damage, is important in cancer treatment and carcinogenesis. Recent studies have suggested that a ubiquitin/proteasome pathway is involved in the repair of topoisomerase I-mediated DNA damage. Activation of this pathway by topoisomerase I-mediated DNA damage results in down-regulation of topoisomerase I and hence tolerance to camptothecin. Many solid tumor cells are defective in topoisomerase I down-regulation, possibly due to a defect in this ubiquitin/proteasome pathway. Defect in this pathway has also been correlated with hypersensitivity to camptothecin. Currently, topoisomerase I-mediated DNA damage has been modeled in a yeast system and components of this ubiqutin/proteasome pathway are being defined genetically and biochemically. In addition to the ubiquitin/proteasome pathway, we have also demonstrated that camptothecin activates the SUMO-1/UBC9 pathway. The roles of the ubiquitin/proteasome and SUMO-1/UBC9 pathways in the repair of topoisomjerase-mediated DNA damage are being actively pursued in this laboratory.

The role of topoisomerase II in tumor cell death and carcinogensis-Many of the most effective anticancer drugs in the clinic such as etoposide and doxorubicin inhibit TOP2. The mechanism of inhibition involves blockage of the religation reaction of TOP2 resulting in protein-linked DNA double-strand breaks and subsequent apoptotic cell death. We have found that TOP2-mediated DNA damage can also be induced by physiological stresses such as oxidative stress, thiol stress and acidic pH. These results have suggested that TOP2-mediated DNA damage may be an integral component of the cell death mechanism induced by various apoptotic stimuli. The molecular mechanisms by which these physiological stresses activate TOP2 are being investigated.

We are also investigating the roles of topoisomerase II in carcinogenesis. The molecular mechanism of TOP2-mediated sequence rearrangement during carcinogenesis is being investigated.