Elevated Akt Activity Protects the Prostate Cancer Cell Line LNCaP from TRAIL-induced Apoptosis

Nesterov, Alexandre; Lu, Xiaojun; Johnson, Michael B.; Miller, Gary J.; Ivashchenko, Yuri; Kraft, Andrew S.

doi:10.1074/jbc.m005196200

Cited by 255 publications

(222 citation statements)

References 57 publications

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199

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“…16 -18 Concentrations of TRAIL up to 4 g/mL can reduce the viability of Du145, PC -3, TsuPr1, and JCA -1 but not LNCaP cells. 18 However, we were unable to confirm a report that Du145 cells are sensitive to 100 ng /mL TRAIL, a difference that may be explained by clonal heterogeneity or the assay method used. 28 The observed TRAIL resistance of prostate cancer cells can be overcome by clinically achievable doses of doxorubicin ( 1 g /mL or 1.84 M).…”

Section: Discussioncontrasting

confidence: 82%

Resistance of prostate cancer cells to soluble TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) can be overcome by doxorubicin or adenoviral delivery of full-length TRAIL

Voelkel‐Johnson

King

Norris³

2002

Cancer Gene Ther

106

100

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Tumor necrosis factor -related apoptosis -inducing ligand ( TRAIL / Apo2L ) has been shown to induce apoptosis in malignant cells without harming normal cells. To determine the antitumor potential of TRAIL against prostate cells, we undertook a comprehensive study that included eight prostate cancer cells lines ( CWR22Rv1, Du145, DuPro, JCA -1, LNCaP, PC -3, PPC -1, and TsuPr1 ) and primary cultures of normal prostate epithelial cells ( PrEC ). Cells were tested for susceptibility to soluble TRAIL in the presence or absence of the chemotherapeutic agent doxorubicin. TRAIL was also delivered by an adenoviral vector. Our results reveal that Du145, DuPro, LNCap, TsuPr1, and PrEC were resistant to 100 ng / mL TRAIL. JCA -1 and PPC -1 were slightly sensitive ( 20% killing ) and PC -3 and CWR22Rv1 exhibited the highest sensitivity to TRAIL ( 30% and 50% killing, respectively ). The combination of 10 ng / mL TRAIL with doxorubicin resulted in 60 -80% cytotoxicity in seven of eight prostate cancer cells. TRAIL -mediated apoptosis involved cleavage of Bid, caspase -3, and PARP, and required caspase -8 and -9 activity. Full -length TRAIL delivered by an adenoviral vector ( AdTRAIL -IRES -GFP ) killed prostate cancer cell lines and PrEC without requisite doxorubicin cotreatment. Therefore, expression of the transgene from a tissue -specific promotor would make gene therapy with AdTRAIL -IRES -GFP a possibility.

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Section: Discussioncontrasting

confidence: 82%

Resistance of prostate cancer cells to soluble TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) can be overcome by doxorubicin or adenoviral delivery of full-length TRAIL

Voelkel‐Johnson

King

Norris³

2002

Cancer Gene Ther

106

100

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“…94 The activation of MAPKs has been linked to integrin-dependent survival in a number of cases. 40,51,57,67,95 Nevertheless, the activation of PI3K/Akt may be more important at regulating cell viability in the presence of unligated integrins, since constitutively active Akt prevents apoptosis induced via death receptors [96][97][98][99][100] or active forms of caspase 8. 101 It is possible that Akt may phosphorylate a peptide loop on caspase 8 proximal to the catalytic site.…”

Section: Signaling Cascades and The Integrin Rheostatmentioning

confidence: 99%

Integrins as a distinct subtype of dependence receptors

Stupack

2005

Cell Death Differ

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In the absence of their cognate ligand, dependence receptors trigger programmed cell death. This function is the defining feature of dependence receptors, which include members of several different protein families. The integrins are a family of heterodimeric receptors for extracellular matrix (ECM) proteins, mediating cell anchorage and migration. Integrins share characteristics with dependence receptors, and integrin binding to substrate ECM ligands is essential for cell survival. Although integrins do not conform in all characteristics to the established definitions of dependence receptors, alterations in the expression of integrins and their ligands during physiological and pathological events, such as wound healing, angiogenesis and tumorigenesis, do regulate cell fate in a ligand-dependent manner. This biosensory function of integrins fits well with our current concept of dependence receptor action, and thus integrins may rightly be considered to comprise a distinct subclass of dependence receptor.

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“…TRAIL resistance has been associated with several factors, including downregulation or loss of death receptors or caspase-8 [4], and overexpression of decoy receptors [5] or intracellular protein c-FLIP [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Multiple effects of TRAIL in human carcinoma cells: Induction of apoptosis, senescence, proliferation, and cytokine production

Levina

Marrangoni

DeMarco

et al. 2008

Experimental Cell Research

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TRAIL is a death ligand that induces apoptosis in malignant but not normal cells. Recently the ability of TRAIL to induce proliferation in apoptosis-resistant normal and malignant cells was reported. In this study, we analyzed TRAIL effects in apoptosis sensitive MCF7, OVCAR3 and H460 human tumor cell lines. TRAIL at low concentrations preferentially induced cell proliferation. At 100 ng/ ml apoptotic death was readily observed, however surviving cells acquired higher proliferative capacity. TRAIL stimulated production of several cytokines, IL-8, RANTES, MCP-1 and bFGF, and activation of caspases 1 and 8 was essential for this effect. Antibodies to IL-8, RANTES, and bFGF blocked TRAIL-induced cell proliferation and further stimulated apoptosis. For the first time, we report that high TRAIL concentrations induced cell senescence as determined by altered morphology and expression of several senescence markers: SA-β-gal, p21 Waf1/Cip1 , p16 INK4a , and HMGA. Caspase 9 inhibition protected TRAIL-treated cells from senescence, whereas inhibition of caspases 1 and 8 increased yield of SLP cells. In conclusion, in cultured human carcinoma cells, TRAIL therapy results in three functional outcomes, apoptosis, proliferation and senescence. TRAIL induced proapoptotic and prosurvival responses correlate with strength of signaling. TRAIL-induced cytokine production is responsible for its proliferative and prosurvival effects.

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Elevated Akt Activity Protects the Prostate Cancer Cell Line LNCaP from TRAIL-induced Apoptosis

Cited by 255 publications

References 57 publications

Resistance of prostate cancer cells to soluble TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) can be overcome by doxorubicin or adenoviral delivery of full-length TRAIL

Resistance of prostate cancer cells to soluble TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) can be overcome by doxorubicin or adenoviral delivery of full-length TRAIL

Integrins as a distinct subtype of dependence receptors

Multiple effects of TRAIL in human carcinoma cells: Induction of apoptosis, senescence, proliferation, and cytokine production

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