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.
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