A novel lung tumor suppressor
Initial Award Abstract
Lung tumors are especially prevalent among smokers, but fortunately, they are potentially very amenable to gene therapy. This gene therapy might be greatly aided by a virus-derived gene known as E1a. We have discovered that E1a is a powerful and broad-range tumor suppressor gene for lung cancer. We will investigate the mechanism of how E1a converts lung cancer cells into normal cells. In future projects, this mechanism will be used to imitate the action of E1 a with biochemicals. This will hopefully generate a new generation of anticancer drugs that work by a novel principle.
E1a has several advantages over most other tumor reducing genes. E1a works regardless (apparently) of which cancer genes caused the tumor; E1a does not kill the tumor cells, but converts them into normal epithelial cells. The converted cells may be exploited to inhibit the growth of neighboring tumor cells. E1a sensitizes tumor cells to programmed cell death apoptosis. This prevents malignancy, both by decreasing the intrinsic malignancy of the tumor cells and by sensitizing them to being killed by chemotherapeutic drugs. E1a's remarkable effects are due to its interactions with a small, well-defined set of target proteins, making it easy to study.
Part of our plan is to identify the cellular target proteins involved in the tumor suppression effect. Knowing the target protein(s), it will be possible to develop (in future projects) other and perhaps more powerful anticancer reagents that work by mimicking E1a. The rest of the plan is to define the specific properties of E1a that may make it useful for an immediate gene therapy approach to lung cancer. These include its ability to induce tumor regression in animals, to generate "bystander" effects on tumor cell eradication, and to sensitize tumors to killing by anticancer drugs. |
Ela protein suppresses the tumor-forming potential of lung cancer cells. - It does this by reprogramming gene--,expression so as to restore a normal complement of epithelial cell proteins. We are working to identify the cellular EIa-interacting proteins responsible for this. ,
During the past year, we have found that Ela induces the expression of epithelial genes by binding to and inactivating a co-repressor protein called CtBP (C-terminal binding protein). This identifies CtBP as a global co-repressor of epithelial genes and provides a new pathway for investigating the loss of epithelial. gene expression in human tumor cells. Indeed, we have also shown that the regulatory region (promoter), bf the E-cadherin gene -- a gene whose expression is frequently host in lung carcinoma cells -- is repressed by CtbP and de-repressed by Ela. Another epithelial. gene promoter, desmocollin-2, behaves similarly.
Normal epithelial cells are programmed to undergo cell death when removed from their extracellular matrix, a phenomenon that we discovered and named "anoikis". The loss of anoikis facilitates tumor progression. El a was able to restore sensitivity to anoWs in several tumor cell lines. We have now found that this is due to the binding of EIa to CtBP, consistent with the idea. that CtBJP is involved in suppressing the epithelial phenotype.
These results will provide new insight into the epithelial phenotype and how it is compromised in human lung cancer cells. This insight will inform new strategies for restoring this normal phenotype and suppressing tumor progression. |