GTMB 7 - Gene Therapy & Molecular Biology

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Sanlioglu et al: Adenovirus mediated gene therapy for prostate carcinomaAt present, death ligands are being evaluated as potentialcancer therapeutic agents (Herr and Debatin, 2001).Previously, several studies using external Fas agonists,anti-Fas antibodies and membrane-bound FasL failed toinduce Fas L mediated apoptosis in prostate cancer cells.Although the down regulation of c-FLIP expressionthrough the use of anti-sense oligonucleotides sensitizedDU145 cells to an anti-Fas monoclonal antibody (Hyer etal, 2002), efficient cell killing was not observed by thisapproach. However, intracellular expression of FasL usingadenoviruses efficiently killed 70-90% of various humanprostate cancer cell lines tested (Hyer et al, 2000).Furthermore, part of this cell killing was attributed to thebystander effect mediated by FasL carried within theapoptotic bodies and cellular debris (Hyer et al, 2003).Despite the fact that human prostate cancer cells expressapoptotic FasL, some of the cell lines, such as LNCaP, areresistant to Fas L mediated cell death. Even so, priorexposure to IFNγ sensitized orthotropic prostate primarytumors to recombinant adenovirus mediated FasL delivery(Selleck et al, 2003). Despite the fact that tumor necrosisfactor (TNF) (Terlikowski, 2001) and FasL (Nagata, 1997)have been studied extensively and were shown toeffectively induce apoptosis in cancer cells, their systemicuse in cancer gene therapy is not recommended due to thesystemic toxicity.With the discovery of a novel death ligand,TRAIL/Apo2L, (Wiley et al, 1995; Pitti et al, 1996) a newera emerged for the deployment of death ligands forcancer gene therapy (Nagane et al, 2001). The fact thatTRAIL does not cause any harm to normal cells but canselectively induce apoptosis in cancer cells brought up thepossibility of TRAIL testing for systemic use (Griffith andLynch, 1998). Five different receptors were identified tointeract with TRAIL; TRAIL-R1, TRAIL-R2, TRAIL-R3,TRAIL-R4 and osteoprotegrin (Abe et al, 2000; Sheikhand Fornace, 2000). TRAIL-R1 and TRAIL-R2 functionas authentic death receptors inducing apoptosis whileTRAIL-R3 and TRAIL-R4 are unable to induce suchsignaling but can serve as decoy receptors (Meng et al,2000). However even today, no single mechanism hasbeen found to account for TRAIL resistance observed innormal cells. The soluble form of TRAIL has successfullybeen tested and no toxicity due to systemic use wasobserved in animal models. However, large quantities ofTRAIL were needed in order to suppress the tumorgrowth. A replication-deficient adenovirus encodinghuman TRAIL (TNFSF10; Ad5-TRAIL) was generated asan alternative to recombinant, soluble TRAIL protein(Griffith and Broghammer, 2001). Ad5-TRAIL infectioninto TRAIL-sensitive prostate tumor cells inducedapoptosis through the activation of Caspase 8 pathways.Normal prostate epithelial cells were not harmed by Ad5-TRAIL infection. Moreover, in vivo Ad5-TRAILadministration suppressed the outgrowth of humanprostate tumor xenografts in SCID mice. Eight prostatecancer cell lines (CWR22Rv1, Du145, DuPro, JCA-1,LNCaP, PC-3, PPC-1, and TsuPr1) and primary culturesof normal prostate epithelial cells (PrEC) were tested forsensitivity to soluble TRAIL induced cell death in anotherstudy (Voelkel-Johnson et al, 2002). 100 ng/mL of solubleTRAIL administration did not induce apoptosis in Du145,DuPro, LNCaP, TsuPr1, and PrEC. Interestingly,treatment with the chemotherapeutic agent doxorubicinsensitized almost all prostate cancer cells to TRAILinducedcell death. On the other hand, an adenoviral vectorexpressing full-length TRAIL (AdTRAIL-IRES-GFP)killed prostate cancer cell lines and, unexpectedly, PrECas well, independent of doxorubicin cotreatment. Thisstudy suggested that the AdTRAIL-IRES-GFP genetherapy approach, complemented with tissue-specificpromoters, would be useful for the treatment of prostatecarcinoma. However, the mechanism of TRAIL resistancein normal cells is not understood and some prostate cancercells appeared to be TRAIL-resistant (Nesterov et al,2001). In one study, ALVA-31, PC-3, and DU 145 celllines were highly sensitive to apoptosis induced byTRAIL, while TSU-Pr1 and JCA-1 cell lines weremoderately sensitive, and the LNCaP cell line wasresistant (Nesterov et al, 2001). Due to the lack of activelipid phosphatase PTEN, LNCaP cells demonstrated aconstitutive Akt activity. Akt is a negative regulator of thephosphatidylinositol (PI)3-kinase/Akt pathway. PI3-kinaseinhibitors sensitized LNCaP prostate cancer cells toTRAIL. In addition, adenovirus expressing a constitutivelyactive Akt reversed the ability of wortmannin to potentiateTRAIL-induced BID cleavage. This suggested thatconstitutive Akt activity inhibits TRAIL-mediatedapoptosis (Nesterov et al, 2001).B. NF-κB inhibiting approaches used tobreakdown TRAIL resistance in prostatecancer cellsThe mechanism of TRAIL induced apoptosis andresistance is outlined in Figure 1. So far, at least twodifferent hypotheses that may partly explain TRAILresistance are asserted. The first hypothesis advocates thatnormal cells carry decoy receptors (TRAIL-R3, TRAIL-R4), which compete with apoptosis inducing TRAILreceptors (TRAIL-R1, TRAIL-R2) for binding to TRAIL(Pan et al, 1997; Sheridan et al, 1997). In this hypothesis,it is believed that decoy receptors either function to diluteout TRAIL ligands (like TRAIL-R3) or supply antiapoptoticsignals (like TRAIL-R4) to cells. As reportedpreviously, TRAIL-R4 binding activates the anti-apoptoticNF-κB signaling pathway, leading to the blockade ofTRAIL induced apoptosis (Degli-Esposti et al, 1997). Inaddition, the expression of decoy receptors is downregulatedin cancer cells through promoterhypermethylation leading to differential sensitivity toTRAIL (van Noesel et al, 2002). However, the linkbetween TRAIL resistance and the expression of decoyreceptors has not been clearly established in human cells(Griffith and Lynch, 1998). Interestingly, activation ofdeath receptors such as TRAIL-R1 and TRAIL-R2 alsostimulated the NF-κB pathway (Chaudhary et al, 1997;Schneider et al, 1997). Under these circumstances, thereason(s) for cells undergoing apoptosis despite theinduction of anti-apoptotic pathways through the samedeath receptors is not fully understood.118
Gene Therapy and Molecular Biology Vol 7, page 119Figure 1: A gene therapy strategy to block anti-apoptotic NF-κB signaling pathway to induce TRAIL sensitivity in prostate cancer cells.Activation of TRAIL receptor 1 (R1) or 2 (R2) by trimeric TRAIL ligands leads to the recruitment of Fas associated death domainprotein (FADD) to the membrane. Then, FADD recruits procaspase 8 to form death inducing signaling complex (DISC). DISC inducedsignaling activates caspase pathway inducing cells into apoptosis. TRAIL receptor 3 (R1) and 4 (R4) serve as decoy receptors. R4activates NF-κB signaling pathways as well. In addition, NF-κB pathway is also activated by R1 and R2 via TNFR-associated deathdomain protein (TRADD) and receptor interacting protein (RIP). Consequently, NF-κB activation augments expressions of various antiapoptoticgenes such as cIAP, BclxL and cFlip in addition to R3. c-Flip, a procaspase 8 homologue, competes with procaspase 8 forbinding to FADD. Thereby it inhibits apoptotic signaling. The expression of adenovirus delivered IKKβKA mutant prevented theactivation of anti-apoptotic NF-κB signaling. This method sensitized prostate cancer cells to TRAIL.The second hypothesis claims the presence of apoptosisinhibitory substances in these cells. Such a molecule,cFLIP (FLICE Inhibitory Protein), a caspase 8 homologue,has been shown to obstruct death ligand induced apoptosis(Irmler et al, 1997; Griffith et al, 1998). Intriguingly, NFκBactivating agents up-regulated cFLIP synthesis (Kreuzet al, 2001). Furthermore, the NF-κB pathway has beenproven to increase TRAIL-R3 synthesis, a decoy receptorfor TRAIL, (Bernard et al, 2001) and the expression ofapoptosis inhibitor Bcl-xL (Hatano and Brenner, 2001;Ravi et al, 2001) resulting in the obstruction of TRAILmediated apoptosis. Apoptosis inhibitors such as cIAP arealso activated by NF-κB pathways (Mitsiades et al, 2002).Based on these results, we can clearly state that the activeNF-κB signaling pathway may provide cells with TRAILresistance by at least four different ways (Figure 1).Additionally, it has been reported that a novel tumorsuppressor gene, PTEN/MMAC1 (Steck et al, 1997;Simpson and Parsons, 2001) negatively regulated TNFinduced NF-κB activity (Ozes et al, 1999; Mayo et al,2002) through the IKK complex (Gustin et al, 2001). Theobservation in which IKK activity is required for PI3K-Akt induced NF-κB activation (Burow et al, 2000;Demarchi et al, 2001) confirmed this report (Madrid et al,2001; Sizemore et al, 2002). Due to a negative correlationbetween the expression of PTEN and the progression ofprostate cancer, advanced prostate cancer cells might haveintrinsically higher NF-κB activity due to the progressiveloss of PTEN. Absence of PTEN function may result inincreased Akt activity induced by PI3K. Since NF-κB is adownstream target for Akt, (Kane et al, 1999;Romashkova and Makarov, 1999; Andjelic et al, 2000;Jones et al, 2000) TRAIL resistance would ultimately beensured in cells by way of the NF-κB pathway. Inagreement with this hypothesis, PTEN sensitized prostatecancer cells to TRAIL induced apoptosis (Yuan andWhang, 2002). Thus, these possible scenarios make NFκBinhibiting vectors such as Ad.IKKβKA (Sanlioglu etal, 2001a) or Ad.IκBαSR (Batra et al, 1999; Sanlioglu andEngelhardt, 1999) ideal candidates for overcoming theTRAIL resistance in PTEN mutant prostate cancer cells. Ina similar manner, TNF induced apoptosis can also beprevented by NF-κB activation as reported (Beg andBaltimore, 1996; Van Antwerp et al, 1996). Previously,NF-κB inhibiting approaches such as adenovirus mediatedtransfer of IKKβ (Ad.IKKβKA) (Sanlioglu et al, 2001a,2001b) or IκBα (Ad.IκBαSR) (Batra et al, 1999;Sanlioglu and Engelhardt, 1999) dominant negativemutants were successfully deployed in order to sensitizelung cancer cells to TNF. Since some tumor cells haveintrinsically high NF-κB activity, which might beresponsible for TRAIL resistance, NF-κB blocking agentscan potentially be useful to overcome TRAIL resistance.For example, a constitutive NF-κB activation wasobserved in renal carcinoma (Oya et al, 2001). Notsurprisingly, melanoma cells having a constitutive NF-κB119
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