Over the decades abundant evidence has emerged to support a causal role for the activated cellular gene, c-myc, in animal and human tumors. In humans, several mechanisms activate the c-myc gene. Chromosomal translocations, which juxtapose the c-myc proto-oncogene at 8q24 to one of three immunoglobulin genes in B-cells, activate the c-myc gene constitutively and thereby promote lymphomagenesis. The c-myc gene is amplified in various human cancers including lung carcinoma, breast carcinoma and in rare cases of colon carcinoma. In addition, elevated expression of the c-myc gene is found in almost one third of breast and colon carcinomas. All of these neoplasms are commonly characterized by the presence of polyploidy, aneuploidy and a propensity to metabolize glucose to lactate in the presence of oxygen (aerobic glycolysis). The c-myc gene encodes an oncogenic helix-loop-helix-leucine zipper transcription factor that acts as a heterodimer with its partner protein, Max, to activate genes regulating the cell cycle machinery as well as critical metabolic enzymes. They have discovered two novel c-Myc mediated apoptotic phenotypes that have therapeutic implications. Through the discovery that c-Myc is able to activate the expression of genes involved in glycolysis, they have observed that c-Myc transformed cells or cells that overexpress lactate dehydrogenase are susceptible to glucose- deprivation induced apoptosis, a pathway that is p53-independent. Whereas normal cells arrest in mitosis when exposed to microtubule inhibitors, the studies reveal that c-Myc is able to uncouple DNA synthesis from mitosis when cells are exposed to colcemid, causing cells to become polyploid and undergo apoptosis. They have exploited this novel phenotype and found that c-Myc protein levels in the NCI 60 cancer cell line panel correlate significantly with the sensitivity of cells to tubulin binding drugs (p-0.001). On the basis of these observations, they set the following specific aims in this renewal application: 1) To determine the effects of c-Myc on hypoxia inducible glycolytic enzyme gene expression and delineate the mechanism of apoptosis induced by glucose deprivation of cells overexpressing c-Myc. 2) To study the efficacy of glycolytic inhibitors in vivo as anti-tumor agents. 3) To determine the mechanism by which c-Myc severs the link between mitosis and DNA synthesis; and 4) To study the effect of paclitaxel and three candidate compounds from the NCI library, whose growth suppressing activities highly correlates with c-Myc protein levels in the 60 cell panel, in in vitro models of c-Myc-induced neoplastic transformation.
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