DcR2 (TRAIL-R4) siRNA and adenovirus delivery of TRAIL (Ad5hTRAIL) break down in vitro tumorigenic potential of prostate carcinoma cells

Abstract

High levels of decoy receptor 2 (DcR2; TRAIL-R4) expression are correlated with TRAIL resistance in prostate cancer cells. In addition, upregulation of TRAIL death receptor (DR4 and DR5) expression, either by ionizing radiation or chemotherapy, can sensitize cancer cells to TRAIL. Considering more than half of human cancers are TRAIL resistant, modulation of surface TRAIL receptor expression appears to be an attractive treatment modality to counteract TRAIL resistance. In this study, three siRNA duplexes targeting DcR2 receptor were tested. Ad5hTRAIL infections were performed to overexpress human full-length TRAIL to induce cell death, and the in vitro tumorigenic potential of prostate cancer cells was assessed using colony-forming assays on soft agar. The DU145 and LNCaP prostate cancer cell lines, which express high levels of DcR2, were resistant to Ad5hTRAIL-induced death. Downregulation of surface DcR2 expression by siRNA sensitized these prostate cancer cell lines to Ad5hTRAIL. In addition, DcR2 siRNA-mediated knockdown of DcR2, followed by Ad5hTRAIL infection, dramatically reduced the in vitro tumorigenic potential of prostate cancer cells. Collectively, our results suggest the potential for combining receptor-specific siRNA with TRAIL in the treatment of certain cancers.

Inhibition of tumor growth and induction of apoptosis in prostate cancer cell lines by overexpression of tissue inhibitor of matrix metalloproteinase-3

“…37,38 Most of them use recombinant adenoviruses or lentiviruses, 39,40 but because of the possibility of recombination with wildtype adenovirus and the antiviral immune response, these approaches have been limited to research use. 41 More recently, electroporation has been applied in vivo and shown to be potentially safe for clinical use.…”

Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level

“…6,7 TRAIL-induced cell death can be specifically inhibited by two membrane-bound antagonistic receptors, TRAIL-R3 (DcR1, LIT or TRID) or TRAIL-R4 (DcR2 or TRUNDD). 2 These receptors have been shown to be expressed and to prevent TRAIL-induced cell death in various human primary tumor cells, including lymphomas, lung, breast and prostate carcinomas, [8][9][10] but the inhibitory potential of this receptor still remains controversial. 11 Although TRAIL-R3 is a GPI-anchored receptor that sequesters TRAIL into lipid rafts, TRAIL-R4 interacts with TRAIL-R2 within the DISC, and impairs caspase-8 processing, 12 thus, inhibiting TRAILinduced apoptosis.…”

Beneficial Effect of Doxazosin on Renal Apoptosis After Partial Bladder Outlet Obstruction

“…Apopto sis is ini ti a ted when the se re cep tors are en ga ged by the ir li gands, that is, Fas li gand, TNF, and TRA -IL, res pec ti vely, which are eit her fre e in the cir cula ti on or bo und to the mem bra ne of cyto to xic ef fec tor cells. [17][18][19][20] Nuc le ar fac tor-kap pa B (NF-kB) ac ti va ti on, in ad di ti on to an in cre a se in the mRNA le vels of TNF-a, TNFR1, cas pa se 8, and cas pa se 3, has be en do cu men ted in rat mo dels of re nal obstruc ti on.…”