E1A oncogene expression inhibits PTHrP P3 promoter activity and sensitizes human prostate cancer cells to TNF-induced apoptosis

Abstract

In the advanced stages of prostate cancer, tumor cells can evolve to become androgen-independent and resistant to injury-induced apoptosis. Tumor cell expression of parathyroid hormone-related protein (PTHrP) may contribute to the apoptosis phenotype. Expression of the adenovirus E1A oncogene repressed PTHrP promoter and mRNA expression in human PC-3 prostate cancer cells and increased the caspase 3 activation and sensitivity of these cells to apoptosis triggered by tumor necrosis factor alpha. These results suggest that strategies aimed at modulating PTHrP expression may increase the efficacy of innate immune effector mechanisms and proapoptotic, therapeutics in prostate cancer.

Understanding and Targeting Osteoclastic Activity in Prostate Cancer Bone Metastases

“…However, an increase in osteoclastogenesis was also observed. These observations along with those of others describe complex interactions dependent on the amount of PTHrP produced, the cells present in the microenvironment, and the differentiation state of all players in the PCa microenvironment (20, 139, 143–147). …”

Parathyroid Hormone-Related Protein (PTHrP): A Key Regulator of Life/Death Decisions by Tumor Cells with Potential Clinical Applications

“…This study suggested potential new targets for therapeutic intervention. Noteworthy, Asadi and collaborators [47] have recently reported that adenovirus E1A oncogene represses PTHrP expression by PC3 prostate cancer cells, thereby decreasing cell survival due to the sensitization to apoptosis. This result could represent a promising starting point for the validation of E1A and/or other modulators of PTHrP expression, as activators of drugs considered per se ineffective in addressing prostate cancer cells to death.…”

Importance of Stromal Stem Cells in Prostate Carcinogenesis Process

“…Normal subjects do not have detectable circulating levels of PTHrP, suggesting that in normal physiology PTHrP acts as a local regulator or cytokine in the tissue where it is produced. Recent evidence suggests the importance of parathyroid hormone-related protein (PTHrP) in tumor progression, androgen-insensitive and resistance of prostate cancer cells to apoptosis (Asadi et al, 1996;Asadi and Kukreja, 2005;Asadi et al, 2010;Wu et al, 1998;Gujral et al, 2001;Tovar and Falzon, 2002). PTHrP is a mediator of cellular growth and differentiation and is involved in mesenchymal-epithelial interactions in several tissues (Hardy, 1992;Van de Stolpe etal, 1993, Wysolmerski etal, 1994.…”

“…Most recently, it has been shown that expression of the adenoviral E1A protein expression in apoptosis-resistant PC-3 cells sensitized these prostate cancer cells to TNF-α-induced apoptotic cell death. Furthermore, it was shown that the effect of E1A on PTHrP expression was through repression of the transcriptional activity of the PTHrP P3 promoter (Asadi et al, 2010). PTHrP transcripts are translated into three different isoforms, PTHrP (-36/139), PTHrP .…”