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Downmodulation of dimethyl transferase activity enhances tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in prostate cancer cells.
Int J Oncol. 2008 Aug; 33(2):381-8.IJ

Abstract

One of the major obstacles in curing prostate cancer is the development of drug resistance. It is not only imperative to discover the molecular basis of resistance but also to find therapeutic agents that can disrupt the resistant pathways. Tumor necrosis factor TNF-related apoptosis-inducing ligand TRAIL-like ligands or agonist TRAIL-receptor monoclonal antibodies have entered phase I and II clinical trials with a very limited cytotoxic profile when used systemically in a variety of cancers. Therefore, TRAIL-receptor agonists are new proapoptotic pharmaceutical agents with great potential as new cancer therapeutic agents. Although many cancer cells undergo TRAIL-mediated apoptosis, some are resistant to TRAIL. Therefore, we have been investigating mechanisms to overcome TRAIL resistance in cancer cells so that TRAIL-associated compounds can be used effectively in clinical trials. Epigenetic inactivation of proapoptotic genes, or activation of survival signaling, can cause cross-resistance to several anti-tumor therapies and to immune cytotoxic lymphocytes. We hypothesize that 5-aza-2 deoxycytidine aza-dCR, decitabine may render TRAIL-resistant prostate cancer cells sensitive to caspase-8-mediated apoptosis and may, therefore, be therapeutically efficient. We evaluated the antiproliferative effects of decitabine on the following four prostate cancer cell lines: well-differentiated AR positive LnCaP p53(+), PTEN- and 22rv1 p53(+) and PTEN(+)]; poorly-differentiated AR negative PC3 p53-, PTEN- and DU145 p53 mutant, PTEN(+). Here, we provide evidence that treatment with sub-optimal concentrations of decitabine are additive to TRAIL effects in well-differentiated PCa cells whereas the same treatment shows synergistic effects in poorly-differentiated PCa cells through increased caspase-8 expression, down-modulation of Akt activation and through the expression of certain anti-apoptotic molecules including FLIP, PED/PEA-15, survivin and c-IAP-1. Our findings demonstrate that decitabine at relatively low concentrations restores caspase-8 expression and sensitises resistant PCa cells to TRAIL-induced apoptosis leading to important implications in novel therapeutic strategies targeting defective apoptosis pathways in advanced prostate tumors.

Authors+Show Affiliations

Department of Experimental Medicine, University of L'Aquila, I-67100 L'Aquila, Italy. festucci@univaq.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

18636160

Citation

Festuccia, Claudio, et al. "Downmodulation of Dimethyl Transferase Activity Enhances Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Prostate Cancer Cells." International Journal of Oncology, vol. 33, no. 2, 2008, pp. 381-8.
Festuccia C, Gravina GL, D'Alessandro AM, et al. Downmodulation of dimethyl transferase activity enhances tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in prostate cancer cells. Int J Oncol. 2008;33(2):381-8.
Festuccia, C., Gravina, G. L., D'Alessandro, A. M., Millimaggi, D., Di Rocco, C., Dolo, V., Ricevuto, E., Vicentini, C., & Bologna, M. (2008). Downmodulation of dimethyl transferase activity enhances tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in prostate cancer cells. International Journal of Oncology, 33(2), 381-8.
Festuccia C, et al. Downmodulation of Dimethyl Transferase Activity Enhances Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Prostate Cancer Cells. Int J Oncol. 2008;33(2):381-8. PubMed PMID: 18636160.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Downmodulation of dimethyl transferase activity enhances tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in prostate cancer cells. AU - Festuccia,Claudio, AU - Gravina,Giovanni Luca, AU - D'Alessandro,Anna Maria, AU - Millimaggi,Danilo, AU - Di Rocco,Cristiana, AU - Dolo,Vincenza, AU - Ricevuto,Enrico, AU - Vicentini,Carlo, AU - Bologna,Mauro, PY - 2008/7/19/pubmed PY - 2008/9/24/medline PY - 2008/7/19/entrez SP - 381 EP - 8 JF - International journal of oncology JO - Int J Oncol VL - 33 IS - 2 N2 - One of the major obstacles in curing prostate cancer is the development of drug resistance. It is not only imperative to discover the molecular basis of resistance but also to find therapeutic agents that can disrupt the resistant pathways. Tumor necrosis factor TNF-related apoptosis-inducing ligand TRAIL-like ligands or agonist TRAIL-receptor monoclonal antibodies have entered phase I and II clinical trials with a very limited cytotoxic profile when used systemically in a variety of cancers. Therefore, TRAIL-receptor agonists are new proapoptotic pharmaceutical agents with great potential as new cancer therapeutic agents. Although many cancer cells undergo TRAIL-mediated apoptosis, some are resistant to TRAIL. Therefore, we have been investigating mechanisms to overcome TRAIL resistance in cancer cells so that TRAIL-associated compounds can be used effectively in clinical trials. Epigenetic inactivation of proapoptotic genes, or activation of survival signaling, can cause cross-resistance to several anti-tumor therapies and to immune cytotoxic lymphocytes. We hypothesize that 5-aza-2 deoxycytidine aza-dCR, decitabine may render TRAIL-resistant prostate cancer cells sensitive to caspase-8-mediated apoptosis and may, therefore, be therapeutically efficient. We evaluated the antiproliferative effects of decitabine on the following four prostate cancer cell lines: well-differentiated AR positive LnCaP p53(+), PTEN- and 22rv1 p53(+) and PTEN(+)]; poorly-differentiated AR negative PC3 p53-, PTEN- and DU145 p53 mutant, PTEN(+). Here, we provide evidence that treatment with sub-optimal concentrations of decitabine are additive to TRAIL effects in well-differentiated PCa cells whereas the same treatment shows synergistic effects in poorly-differentiated PCa cells through increased caspase-8 expression, down-modulation of Akt activation and through the expression of certain anti-apoptotic molecules including FLIP, PED/PEA-15, survivin and c-IAP-1. Our findings demonstrate that decitabine at relatively low concentrations restores caspase-8 expression and sensitises resistant PCa cells to TRAIL-induced apoptosis leading to important implications in novel therapeutic strategies targeting defective apoptosis pathways in advanced prostate tumors. SN - 1019-6439 UR - https://www.unboundmedicine.com/medline/citation/18636160/Downmodulation_of_dimethyl_transferase_activity_enhances_tumor_necrosis_factor_related_apoptosis_inducing_ligand_induced_apoptosis_in_prostate_cancer_cells_ L2 - http://www.spandidos-publications.com/ijo/33/2/381 DB - PRIME DP - Unbound Medicine ER -