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Signaling pathway activated during apoptosis of the prostate cancer cell line LNCaP: overexpression of caspase-7 as a new gene therapy strategy for prostate cancer.
Cancer Res. 1999 Jan 15; 59(2):382-90.CR

Abstract

We studied the molecular mechanisms of apoptosis in the prostate cancer cell line LNCaP and whether overexpression of caspase activity could force this cell line to undergo apoptosis. The inhibitor of phosphomevalonate decarboxylase, sodium phenylacetate, and the protein kinase inhibitor staurosporine induced (a) release of cytochrome c from the mitochondria to the cytosol; (b) reduction in mitochondrial transmembrane potential; (c) proteolytic processing of caspase-3 and -7 but not -2; (d) cleavage of the DEVD substrate and the death substrates poly(ADP-ribose) polymerase and DNA fragmentation factor; and (e) apoptosis. The panspecific inhibitor of caspase activation N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (z-VAD-FMK) prevented all of these events except release of mitochondrial cytochrome c into the cytosol. None of these apoptotic signaling events were elicited by staurosporine or sodium phenylacetate treatment of LNCaP-Bcl-2 cells that overexpress the oncoprotein Bcl-2. Because caspase-7 is activated in every model of apoptosis that we have characterized thus far, we wished to learn whether overexpression of this protease could directly cause apoptosis of LNCaP cells. By using a replication-defective adenovirus, overexpression of caspase-7 protein in both LNCaP and LNCaP-Bcl-2 cells was accompanied by induction of cleavage of the DEVD substrate and TUNEL. These studies have demonstrated that caspase-7 and -3 are critical mediators of apoptosis in LNCaP cells. Caspase-7 was proteolytically activated in every model of apoptosis that we have developed, and the overexpression of it induced apoptosis of LNCaP and LNCaP-Bcl-2 cells. Thus, adenoviral-mediated transfer of caspase-7 may offer a new effective approach for the treatment of prostate cancer.

Authors+Show Affiliations

Department of Medicine, Veterans Administration Medical Center and Baylor College of Medicine, Houston, Texas 77030, USA. marcelli@bcm.tmc.eduNo affiliation info availableNo 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
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

9927051

Citation

Marcelli, M, et al. "Signaling Pathway Activated During Apoptosis of the Prostate Cancer Cell Line LNCaP: Overexpression of Caspase-7 as a New Gene Therapy Strategy for Prostate Cancer." Cancer Research, vol. 59, no. 2, 1999, pp. 382-90.
Marcelli M, Cunningham GR, Walkup M, et al. Signaling pathway activated during apoptosis of the prostate cancer cell line LNCaP: overexpression of caspase-7 as a new gene therapy strategy for prostate cancer. Cancer Res. 1999;59(2):382-90.
Marcelli, M., Cunningham, G. R., Walkup, M., He, Z., Sturgis, L., Kagan, C., Mannucci, R., Nicoletti, I., Teng, B., & Denner, L. (1999). Signaling pathway activated during apoptosis of the prostate cancer cell line LNCaP: overexpression of caspase-7 as a new gene therapy strategy for prostate cancer. Cancer Research, 59(2), 382-90.
Marcelli M, et al. Signaling Pathway Activated During Apoptosis of the Prostate Cancer Cell Line LNCaP: Overexpression of Caspase-7 as a New Gene Therapy Strategy for Prostate Cancer. Cancer Res. 1999 Jan 15;59(2):382-90. PubMed PMID: 9927051.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Signaling pathway activated during apoptosis of the prostate cancer cell line LNCaP: overexpression of caspase-7 as a new gene therapy strategy for prostate cancer. AU - Marcelli,M, AU - Cunningham,G R, AU - Walkup,M, AU - He,Z, AU - Sturgis,L, AU - Kagan,C, AU - Mannucci,R, AU - Nicoletti,I, AU - Teng,B, AU - Denner,L, PY - 1999/2/2/pubmed PY - 1999/2/2/medline PY - 1999/2/2/entrez SP - 382 EP - 90 JF - Cancer research JO - Cancer Res VL - 59 IS - 2 N2 - We studied the molecular mechanisms of apoptosis in the prostate cancer cell line LNCaP and whether overexpression of caspase activity could force this cell line to undergo apoptosis. The inhibitor of phosphomevalonate decarboxylase, sodium phenylacetate, and the protein kinase inhibitor staurosporine induced (a) release of cytochrome c from the mitochondria to the cytosol; (b) reduction in mitochondrial transmembrane potential; (c) proteolytic processing of caspase-3 and -7 but not -2; (d) cleavage of the DEVD substrate and the death substrates poly(ADP-ribose) polymerase and DNA fragmentation factor; and (e) apoptosis. The panspecific inhibitor of caspase activation N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (z-VAD-FMK) prevented all of these events except release of mitochondrial cytochrome c into the cytosol. None of these apoptotic signaling events were elicited by staurosporine or sodium phenylacetate treatment of LNCaP-Bcl-2 cells that overexpress the oncoprotein Bcl-2. Because caspase-7 is activated in every model of apoptosis that we have characterized thus far, we wished to learn whether overexpression of this protease could directly cause apoptosis of LNCaP cells. By using a replication-defective adenovirus, overexpression of caspase-7 protein in both LNCaP and LNCaP-Bcl-2 cells was accompanied by induction of cleavage of the DEVD substrate and TUNEL. These studies have demonstrated that caspase-7 and -3 are critical mediators of apoptosis in LNCaP cells. Caspase-7 was proteolytically activated in every model of apoptosis that we have developed, and the overexpression of it induced apoptosis of LNCaP and LNCaP-Bcl-2 cells. Thus, adenoviral-mediated transfer of caspase-7 may offer a new effective approach for the treatment of prostate cancer. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/9927051/Signaling_pathway_activated_during_apoptosis_of_the_prostate_cancer_cell_line_LNCaP:_overexpression_of_caspase_7_as_a_new_gene_therapy_strategy_for_prostate_cancer_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9927051 DB - PRIME DP - Unbound Medicine ER -