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Abstract
A significant percentage of prostate tumors have amplifications of the c-Myc gene, but the precise role of c-Myc in prostate cancer is not fully understood. Immortalization of human epithelial cells involves both inactivation of the Rb/p16INK4a pathway and telomere maintenance, and it has been recapitulated in culture by expression of the catalytic subunit of telomerase, hTERT, in combination with viral oncoproteins. Here, we show the immortalization of human prostate epithelial cells (HPrEC) by a single genetic event, the expression of the c-Myc oncogene. Myc stabilizes telomere length in HPrEC through up-regulation of hTERT expression and overrides the accumulation of cell cycle inhibitory proteins, such as p16INK4a. Overall, HPrECs expressing c-Myc retain many characteristics of normal cells, such as the induction of a senescence-like growth arrest in response to oncogenic Ras, an intact p53 response, and an absence of gross karyotypic abnormalities. However, HPrECs expressing c-Myc lack a Rb/p16INK4a checkpoint and can be transformed without the need for additional genetic lesions in that pathway. These results give a partial explanation for the physiologic role of c-Myc overexpression in prostate cancer.
Highlights
Normal human somatic cells undergo a limited number of divisions before entering an irreversible growth arrest state defined as replicative senescence [1]
human prostate epithelial cells (HPrEC) at PD f10 were infected with retroviral vectors expressing either green fluorescent protein, the catalytic subunit of telomerase, c-Myc, Mdm2, human papillomavirus 16 E7, or both human papillomavirus 16 E6 and E7
As shown previously in other human cell types [12], we found that in HPrEC immortalized by hTERT, addition of oncogenic Ras, E6 + E7, and SV40 small t enabled them to grow in soft agar (Fig. 6D)
Summary
Normal human somatic cells undergo a limited number of divisions before entering an irreversible growth arrest state defined as replicative senescence [1]. This life span varies between different cell types and is dependent on culture conditions [2]. RasV12 or c-Myc into primary cells has been shown to result in up-regulation of both p16INK4a and p14ARF [17, 43,44,45] and this holds true for HPrEC. The p14ARF levels were significantly elevated by Myc and Ras, this had no discernible effect on the viability of the cells following treatment with Adriamycin (Fig. 6B). C-Myc or the combination of Myc, Ras, and SV40 small t antigen (see below) did not seem to alter the viability of the HPrEC cells under these conditions
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