Cancer is a disease of deregulated proliferation as well as suppressed cell death. The molecular alterations that provide selective tumor cell killings by a variety of anticancer drugs are currently unknown; however, it is now believed that diverse chemotherapeutic drugs induce cytotoxicity by utilizing intrinsic apoptotic (programmed cell death) pathways in the cells. Most anticancer drugs target DNA synthesis to induce DNA damage and, eventually, apoptosis. Therefore, the effectiveness of these agents largely depends on the cell’s ability to detect and respond to this damage. However, the key player in DNA damage-induced apoptosis, the p53 tumor suppressor gene, has been found to be functionally inactive in more than 50% of cancers. Other major classes of chemotherapeutic agents target cell metabolism or division, which can induce cell death through a p53-independent pathway, thereby eliminating the requirement for functional p53 in cancer cells. Microtubule-disrupting agents such as vinblastine, vincristine, nocodazole, and paclitaxel are among such chemotherapeutic agents that are increasingly used to effectively treat cancers, including p53-deficient tumors.
The pathway leading to apoptosis utilizes a variety of signaling mechanisms including the MAP kinase pathways and the activation of proteases. As part of a research collaboration with Professor Genhong Cheng's laboratory at UCLA, we identified MEKK1, a major player of the MAP kinase cascade, to be involved in vinblastine-induced apoptosis in B cells. We have created knock out mekk1 chicken DT40 B-cells which will be used as model system in my lab. We showed that DT40 cells with targeted disruption of the MEKK1 gene become completely resistant to cell apoptosis induced by anti-microtubule agents. Mutation or downregulation of MEKK1 gene, or genes modulated by MEKK1, are expected to constitute a potential mechanism for the development of the observed chemoresistance in cancer patients.
1. Erin Tricker, Afsane Arvand, Raymond Kwan, and Genhong Cheng. Apoptosis Induced by Cytoskeletal Distribution Requires Distinct Domains of MEKK1. (Pending) Submitted to JBC, 2010.
2. Arvand, A., Denny, CT. Biology of EWS/ETS fusions in Ewing’s family tumors. Oncogene 20, 5747-5754, 2001.
3. Scott M Welford, Stephen P. Hebert, Benjamin Deneen, Afsane Arvand, and Christopher T. Denny. DNA binding domain independent pathways are involved in EWS/FLI1 mediated oncogenesis. Journal of Biochemistry, 276 (45) 41977-41984, 2001.
4. Arvand, A., Welford, S.W., Teitell, MA, and Denny C.T. The C-terminal domain of FLI1 is necessary for full tumorigenic potential of the EWS/FLI1 oncogene. Cancer Research, 61, 5311-5317 July 1, 2001.
5. Thompson, Ad, Teitell, MA, Arvand, A., and Denny C.T. Divergent Ewing's sarcoma EWS/ETS fusions share overlapping biologic activities and confer a distinctive tumorigenic phenotype on NIH 3T3 cells. Oncogene 18, 5506-5513, 1999.
6. Arvand, A., Bastians, H., Welford, S.M., Thompson, A.D., Ruderman, J.V., and Denny, C.T. EWS/FLI 1 up regulates mE2-C, a cyclin-selective ubiquitin-conjugating enzyme involved in cyclin B destruction. Oncogene 17, 2039-2045, 1998.
7. May, W.A., Arvand, A., Thompson, A., Braun, BS, Wright, M. and Denny, C.T. EWS/FLI 1-induced manic fringe renders NIH 3T3 cells tumorigenic. Nature Genetics 17, 495-497, 1997.
8. Thompson, A.D., Braun, BS, Arvand, A., Stewart, S.D., May, W.A., Chen, E., Korenberg, J., and Denny, C.T. Eat-2 is a novel SH2 domain containing protein that is up regulated by Ewing's sarcoma EWS/FLI fusion gene. Oncogene 13, 2649-2658. 1996.