Adenovirus-mediated ikkβka expression sensitizes prostate carcinoma cells to trail-induced apoptosis

ABSTRACT Despite the fact that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in cancer cells, TRAIL resistance in cancer cells has

challenged the use of TRAIL as a therapeutic agent. First, prostate carcinoma cell lines (DU145, LNCaP and PC3) were screened for sensitivity to adenovirus delivery of TRAIL (Ad5hTRAIL). As

amplified Ikappa B kinase (IKK) activity is responsible for the constitutive nuclear factor-_κ_B (NF-_κ_B) activation leading to uncontrolled cell growth and metastasis, a dual vector

approach using both an adenovirus vector (Ad) expressing the dominant-negative mutant of IKK_β_ (AdIKK_β_KA) and Ad5hTRAIL was employed to determine if prostate cancer cells were sensitized

to TRAIL in the setting of IKK inhibition. Inhibition of the NF-_κ_B pathway through IKK blockade sensitized all three prostate cancer cell lines to TRAIL, regardless of NF-_κ_B activation

or decoy receptor gene expression. Moreover, a novel quantitative real-time RT-PCR assay and conventional flow cytometry analysis indicated that TRAIL-resistant DU145 and LNCaP cells, but

not TRAIL-sensitive PC3 cells, expressed substantial amounts of TRAIL Decoy Receptor 4. In conclusion, TRAIL decoy receptor expression appeared to be the chief determinant of TRAIL

resistance encountered in prostate carcinoma cell lines. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS

OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online access $259.00 per year only $21.58 per issue Learn more Buy this article * Purchase on

SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about

institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS FERROPTOSIS ENHANCES THE THERAPEUTIC POTENTIAL OF ONCOLYTIC ADENOVIRUSES KD01

AGAINST CANCER Article Open access 03 March 2025 NON-APOPTOTIC FUNCTION OF CASPASE-8 CONFERS PROSTATE CANCER ENZALUTAMIDE RESISTANCE VIA NF-ΚB ACTIVATION Article Open access 04 September

2021 HARNESSING TRAIL-INDUCED CELL DEATH FOR CANCER THERAPY: A LONG WALK WITH THRILLING DISCOVERIES Article Open access 04 October 2022 REFERENCES * Levine AJ . p53, the cellular gatekeeper

for growth and division. _Cell_ 1997; 88 (3): 323–331. Article  CAS  PubMed  Google Scholar  * Zeimet AG, Riha K, Berger J, Widschwendter M, Hermann M, Daxenbichler G et al. New insights

into p53 regulation and gene therapy for cancer. _Biochem Pharmacol_ 2000; 60 (8): 1153–1163. Article  CAS  PubMed  Google Scholar  * Obata A, Eura M, Sasaki J, Saya H, Chikamatsu K, Tada M

et al. Clinical significance of p53 functional loss in squamous cell carcinoma of the oropharynx. _Int J Cancer_ 2000; 89 (2): 187–193. Article  CAS  PubMed  Google Scholar  * Ehlert JE,

Kubbutat MH . Apoptosis and its relevance in cancer therapy. _Onkologie_ 2001; 24 (5): 433–440. CAS  PubMed  Google Scholar  * Kelley SK, Ashkenazi A . Targeting death receptors in cancer

with Apo2L/TRAIL. _Curr Opin Pharmacol Aug_ 2004; 4 (4): 333–339. Article  CAS  Google Scholar  * Chopin V, Slomianny C, Hondermarck H, Le Bourhis X . Synergistic induction of apoptosis in

breast cancer cells by cotreatment with butyrate and TNF-alpha, TRAIL, or anti-Fas agonist antibody involves enhancement of death receptors' signaling and requires P21(waf1). _Exp Cell

Res_ 2004; 298 (2): 560–573. Article  CAS  PubMed  Google Scholar  * Terlikowski SJ . Tumour necrosis factor and cancer treatment: a historical review and perspectives. _Rocz Akad Med

Bialymst_ 2001; 46: 5–18. CAS  PubMed  Google Scholar  * Shiraishi T, Suzuyama K, Okamoto H, Mineta T, Tabuchi K, Nakayama K et al. Increased cytotoxicity of soluble Fas ligand by fusing

isoleucine zipper motif. _Biochem Biophys Res Commun_ 2004; 322 (1): 197–202. Article  CAS  PubMed  Google Scholar  * Jin H, Yang R, Fong S, Totpal K, Lawrence D, Zheng Z et al. Apo2

ligand/tumor necrosis factor-related apoptosis-inducing ligand cooperates with chemotherapy to inhibit orthotopic lung tumor growth and improve survival. _Cancer Res_ 2004; 64 (14):

4900–4905. Article  CAS  PubMed  Google Scholar  * Griffith TS, Lynch DH . TRAIL: a molecule with multiple receptors and control mechanisms. _Curr Opin Immunol_ 1998; 10 (5): 559–563.

Article  CAS  PubMed  Google Scholar  * Nesterov A, Lu X, Johnson M, Miller GJ, Ivashchenko Y, Kraft AS . Elevated AKT activity protects the prostate cancer cell line LNCaP from

TRAIL-induced apoptosis. _J Biol Chem_ 2001; 276 (14): 10767–10774. Article  CAS  PubMed  Google Scholar  * Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D et al. Control

of TRAIL-induced apoptosis by a family of signaling and decoy receptors. _Science_ 1997; 277 (5327): 818–821. Article  CAS  PubMed  Google Scholar  * van Noesel MM, van Bezouw S, Salomons

GS, Voute PA, Pieters R, Baylin SB et al. Tumor-specific down-regulation of the tumor necrosis factor-related apoptosis-inducing ligand decoy receptors DcR1 and DcR2 is associated with dense

promoter hypermethylation. _Cancer Res_ 2002; 62 (7): 2157–2161. CAS  PubMed  Google Scholar  * Griffith TS, Chin WA, Jackson GC, Lynch DH, Kubin MZ . Intracellular regulation of

TRAIL-induced apoptosis in human melanoma cells. _J Immunol_ 1998; 161 (6): 2833–2840. CAS  PubMed  Google Scholar  * Shankar S, Chen X, Srivastava RK . Effects of sequential treatments with

chemotherapeutic drugs followed by TRAIL on prostate cancer _in vitro_ and _in vivo_. _Prostate_ 2005; 62 (2): 165–186. Article  CAS  PubMed  Google Scholar  * Kelly MM, Hoel BD,

Voelkel-Johnson C . Doxorubicin pretreatment sensitizes prostate cancer cell lines to TRAIL induced apoptosis which correlates with the loss of c-FLIP expression. _Cancer Biol Ther_ 2002; 1

(5): 520–527. Article  PubMed  Google Scholar  * Voelkel-Johnson C . An antibody against DR4 (TRAIL-R1) in combination with doxorubicin selectively kills malignant but not normal prostate

cells. _Cancer Biol Ther_ 2003; 2 (3): 283–290. Article  CAS  PubMed  Google Scholar  * Guseva NV, Taghiyev AF, Sturm MT, Rokhlin OW, Cohen MB . Tumor necrosis factor-related

apoptosis-inducing ligand-mediated activation of mitochondria-associated nuclear factor-kappaB in prostatic carcinoma cell lines. _Mol Cancer Res_ 2004; 2 (10): 574–584. CAS  PubMed  Google

Scholar  * Bernard D, Quatannens B, Vandenbunder B, Abbadie C . Rel/NF-kappaB transcription factors protect against tumor necrosis factor (TNF)-related apoptosis-inducing ligand

(TRAIL)-induced apoptosis by up-regulating the TRAIL decoy receptor DcR1. _J Biol Chem_ 2001; 276 (29): 27322–27328. Article  CAS  PubMed  Google Scholar  * Hatano E, Brenner DA . Akt

protects mouse hepatocytes from TNF-alpha- and Fas-mediated apoptosis through NK-kappa B activation. _Am J Physiol Gastrointest Liver Physiol_ 2001; 281 (6): G1357–1368. Article  CAS  PubMed

  Google Scholar  * Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T et al. Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic

applications. _Blood_ 2002; 99 (11): 4079–4086. Article  CAS  PubMed  Google Scholar  * Kreuz S, Siegmund D, Scheurich P, Wajant H . NF-kappaB inducers upregulate cFLIP, a

cycloheximide-sensitive inhibitor of death receptor signaling. _Mol Cell Biol_ 2001; 21 (12): 3964–3973. Article  CAS  PubMed  PubMed Central  Google Scholar  * Degli-Esposti MA, Dougall WC,

Smolak PJ, Waugh JY, Smith CA, Goodwin RG . The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. _Immunity_

1997; 7 (6): 813–820. Article  CAS  PubMed  Google Scholar  * Schneider P, Thome M, Burns K, Bodmer JL, Hofmann K, Kataoka T et al. TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent

apoptosis and activate NF-kappaB. _Immunity_ 1997; 7 (6): 831–836. Article  CAS  PubMed  Google Scholar  * Chaudhary PM, Eby M, Jasmin A, Bookwalter A, Murray J, Hood L . Death receptor 5, a

new member of the TNFR family, and DR4 induce FADD- dependent apoptosis and activate the NF-kappaB pathway. _Immunity_ 1997; 7 (6): 821–830. Article  CAS  PubMed  Google Scholar  *

Sanlioglu S, Williams CM, Samavati L, Butler NS, Wang G, McCray PB et al. Lipopolysaccharide induces Rac1-dependent reactive oxygen species formation and coordinates tumor necrosis

factor-alpha secretion through IKK regulation of NF-kappa B. _J Biol Chem_ 2001; 276 (32): 30188–30198. Article  CAS  PubMed  Google Scholar  * Sanlioglu S, Luleci G, Thomas KW .

Simultaneous inhibition of Rac1 and IKK pathways sensitizes lung cancer cells to TNFalpha-mediated apoptosis. _Cancer Gene Ther_ 2001; 8 (11): 897–905. Article  CAS  PubMed  Google Scholar 

* Sanlioglu AD, Koksal T, Baykara M, Luleci G, Karacay B, Sanlioglu S . Current progress in adenovirus mediated gene therapy for patients with prostate carcinoma. _Gene Ther Mol Biol_ 2003;

7: 113–133. Google Scholar  * Griffith TS, Anderson RD, Davidson BL, Williams RD, Ratliff TL . Adenoviral-mediated transfer of the TNF-related apoptosis-inducing ligand/Apo-2 ligand gene

induces tumor cell apoptosis. _J Immunol_ 2000; 165 (5): 2886–2894. Article  CAS  PubMed  Google Scholar  * Sanlioglu S, Engelhardt JF . Cellular redox state alters recombinant

adeno-associated virus transduction through tyrosine phosphatase pathways. _Gene Therapy_ 1999; 6 (8): 1427–1437. Article  CAS  PubMed  Google Scholar  * Engelhardt JF, Yang Y,

Stratford-Perricaudet LD, Allen ED, Kozarsky K, Perricaudet M et al. Direct gene transfer of human CFTR into human bronchial epithelia of xenografts with E1-deleted adenoviruses. _Nat Genet_

1993; 4 (1): 27–34. Article  CAS  PubMed  Google Scholar  * Karacay B, Sanlioglu S, Griffith TS, Sandler A, Bonthius DJ . Inhibition of the NF-kappaB pathway enhances TRAIL-mediated

apoptosis in neuroblastoma cells. _Cancer Gene Ther_ 2004; 11 (10): 681–690. Article  CAS  PubMed  Google Scholar  * Oya M, Ohtsubo M, Takayanagi A, Tachibana M, Shimizu N, Murai M .

Constitutive activation of nuclear factor-kappaB prevents TRAIL-induced apoptosis in renal cancer cells. _Oncogene_ 2001; 20 (29): 3888–3896. Article  CAS  PubMed  Google Scholar  * Franco

AV, Zhang XD, Van Berkel E, Sanders JE, Zhang XY, Thomas WD et al. The role of NF-kappa B in TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of melanoma cells. _J Immunol_

2001; 166 (9): 5337–5345. Article  CAS  PubMed  Google Scholar  * Sanlioglu AD, Aydin C, Bozcuk H, Terzioglu E, Sanlioglu S . Fundamental principals of tumor necrosis factor-alpha gene

therapy approach and implications for patients with lung carcinoma. _Lung Cancer_ 2004; 44 (2): 199–211. Article  PubMed  Google Scholar  * Gasparian AV, Yao YJ, Kowalczyk D, Lyakh LA,

Karseladze A, Slaga TJ et al. The role of IKK in constitutive activation of NF-kappaB transcription factor in prostate carcinoma cells. _J Cell Sci_ 2002; 115 (Part 1): 141–151. CAS  PubMed

  Google Scholar  * Batra RK, Guttridge DC, Brenner DA, Dubinett SM, Baldwin AS, Boucher RC . IkappaBalpha gene transfer is cytotoxic to squamous-cell lung cancer cells and sensitizes them

to tumor necrosis factor-alpha-mediated cell death. _Am J Respir Cell Mol Biol_ 1999; 21 (2): 238–245. Article  CAS  PubMed  Google Scholar  * Andjelic S, Hsia C, Suzuki H, Kadowaki T,

Koyasu S, Liou HC . Phosphatidylinositol 3-kinase and NF-kappa B/Rel are at the divergence of CD40-mediated proliferation and survival pathways. _J Immunol_ 2000; 165 (7): 3860–3867. Article

  CAS  PubMed  Google Scholar  * Jones RG, Parsons M, Bonnard M, Chan VS, Yeh WC, Woodgett JR et al. Protein kinase B regulates T lymphocyte survival, nuclear factor kappaB activation, and

Bcl-X(L) levels _in vivo_. _J Exp Med_ 2000; 191 (10): 1721–1734. Article  CAS  PubMed  PubMed Central  Google Scholar  * Demarchi F, Verardo R, Varnum B, Brancolini C, Schneider C . Gas6

anti-apoptotic signaling requires NF-kappa B activation. _J Biol Chem_ 2001; 276 (34): 31738–31744. Article  CAS  PubMed  Google Scholar  * Voelkel-Johnson C, King DL, Norris JS . 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. _Cancer Gene Ther_ 2002;

9 (2): 164–172. Article  CAS  PubMed  Google Scholar  * Beresford SA, Davies MA, Gallick GE, Donato NJ . Differential effects of phosphatidylinositol–3/Akt-kinase inhibition on apoptotic

sensitization to cytokines in LNCaP and PCc-3 prostate cancer cells. _J Interferon Cytokine Res_ 2001; 21 (5): 313–322. Article  CAS  PubMed  Google Scholar  * Shankar S, Singh TR,

Srivastava RK . Ionizing radiation enhances the therapeutic potential of TRAIL in prostate cancer _in vitro_ and _in vivo_: intracellular mechanisms. _Prostate_ 2004; 61 (1): 35–49. Article

  CAS  PubMed  Google Scholar  * Singh TR, Shankar S, Chen X, Asim M, Srivastava RK . Synergistic interactions of chemotherapeutic drugs and tumor necrosis factor-related apoptosis-inducing

ligand/Apo-2 ligand on apoptosis and on regression of breast carcinoma _in vivo_. _Cancer Res_ 2003; 63 (17): 5390–5400. CAS  PubMed  Google Scholar  * Shivapurkar N, Toyooka S, Toyooka KO,

Reddy J, Miyajima K, Suzuki M et al. Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types. _Int J Cancer_ 2004; 109 (5): 786–792. Article  CAS  PubMed 

Google Scholar  * Perlman H, Nguyen N, Liu H, Eslick J, Esser S, Walsh K et al. Rheumatoid arthritis synovial fluid macrophages express decreased tumor necrosis factor-related

apoptosis-inducing ligand R2 and increased decoy receptor tumor necrosis factor-related apoptosis-inducing ligand R3. _Arthritis Rheum_ 2003; 48 (11): 3096–3101. Article  PubMed  Google

Scholar  * Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM . An antagonist decoy receptor and a death domain-containing receptor for TRAIL. _Science_ 1997; 277 (5327): 815–818. Article  CAS 

PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We thank Dan Bonthius, MD, PhD for his help in critical reading and editing the manuscript. This work is supported by grants from

the Akdeniz University Scientific Research Project Administration Division and Health Science Institute (to SS) and is a part of ADS's PhD thesis. AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * Human Gene Therapy Unit, Akdeniz University, Faculty of Medicine, Antalya, Turkey A D Sanlioglu, I T Koksal, B Karacay, M Baykara, G Luleci & S Sanlioglu * Department of

Medical Biology and Genetics, Akdeniz University, Faculty of Medicine, Antalya, Turkey A D Sanlioglu, G Luleci & S Sanlioglu * Department of Urology, Akdeniz University, Faculty of

Medicine, Antalya, Turkey I T Koksal & M Baykara * Center for Gene Therapy at the University of Iowa, Iowa City, IA, USA B Karacay Authors * A D Sanlioglu View author publications You

can also search for this author inPubMed Google Scholar * I T Koksal View author publications You can also search for this author inPubMed Google Scholar * B Karacay View author publications

You can also search for this author inPubMed Google Scholar * M Baykara View author publications You can also search for this author inPubMed Google Scholar * G Luleci View author

publications You can also search for this author inPubMed Google Scholar * S Sanlioglu View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING

AUTHOR Correspondence to S Sanlioglu. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Sanlioglu, A., Koksal, I., Karacay, B. _et al._ Adenovirus-mediated

IKK_β_KA expression sensitizes prostate carcinoma cells to TRAIL-induced apoptosis. _Cancer Gene Ther_ 13, 21–31 (2006). https://doi.org/10.1038/sj.cgt.7700877 Download citation * Received:

11 January 2005 * Revised: 20 April 2005 * Accepted: 01 May 2005 * Published: 29 July 2005 * Issue Date: 01 January 2006 * DOI: https://doi.org/10.1038/sj.cgt.7700877 SHARE THIS ARTICLE

Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided

by the Springer Nature SharedIt content-sharing initiative KEYWORDS * prostate carcinoma * TRAIL resistance * decoy receptors * IKK