High susceptibility of metastatic cells derived from human prostate and colon cancer cells to TRAIL and sensitization of TRAIL-insensitive primary cells to TRAIL by 4,5-dimethoxy-2-nitrobenzaldehyde

Abstract

BackgroundTumor recurrence and metastasis develop as a result of tumors' acquisition of anti-apoptotic mechanisms and therefore, it is necessary to develop novel effective therapeutics against metastatic cancers. In this study, we showed the differential TRAIL responsiveness of human prostate adenocarcinoma PC3 and human colon carcinoma KM12 cells and their respective highly metastatic PC3-MM2 and KM12L4A sublines and investigated the mechanism underlying high susceptibility of human metastatic cancer cells to TRAIL.ResultsPC3-MM2 and KM12L4A cells with high level of c-Myc and DNA-PKcs were more susceptible to TRAIL than their poorly metastatic primary PC3 and KM12 cells, which was associated with down-regulation of c-FLIPL/S and Mcl-1 and up-regulation of the TRAIL receptor DR5 but not DR4 in both metastatic cells. Moreover, high susceptibility of these metastatic cells to TRAIL was resulted from TRAIL-induced potent activation of caspase-8, -9, and -3 in comparison with their primary cells, which led to cleavage and down-regulation of DNA-PKcs. Knockdown of c-Myc gene in TRAIL-treated PC3-MM2 cells prevented the increase of DR5 cell surface expression, caspase activation and DNA-PKcs cleavage and attenuated the apoptotic effects of TRAIL. Moreover, the suppression of DNA-PKcs level with siRNA in the cells induced the up-regulation of DR5 and active caspase-8, -9, and -3. We also found that 4,5-dimethoxy-2-nitrobenzaldehyde (DMNB), a specific inhibitor of DNA-PK, potentiated TRAIL-induced cytotoxicity and apoptosis in relatively TRAIL-insensitive PC3 and KM12 cells and therefore functioned as a TRAIL sensitizer.ConclusionThis study showed the positive relationship between c-Myc expression in highly metastatic human prostate and colon cancer cells and susceptibility to TRAIL-induced apoptosis and therefore indicated that TRAIL might be used as an effective therapeutic modality for advanced metastatic cancers overexpressing c-Myc and combination of TRAIL therapy with agent that inhibits the DNA-PKcs/Akt signaling pathway might be clinically useful for the treatment of relatively TRAIL-insensitive human cancers.

TRAIL and guardian angel of genome integrity: ATM boards TRAIL blazer

“…Abrogation of DNA-PKcs in the cells induced the upregulation of DR5 and active caspase-8, -9, and -3. In accordance with the same approach, 4, 5-dimethoxy-2-nitrobenzaldehyde (DMNB), a specific inhibitor of DNA-PK, potentiated TRAIL-induced cytotoxicity and apoptosis in relatively TRAIL-insensitive KM12 and PC3 cells Kim et al (2011). Consistent with the same concept, K562/R3 cells, a stable TRAIL-sensitive variant isolated from human K562 leukemic cells, displayed down regulation of DNA-PK/Akt pathway and a high responsiveness to TRAILmediated growth inhibition and apoptosis.…”

Amurensin G enhances the susceptibility to tumor necrosis factor‐related apoptosis‐inducing ligand‐mediated cytotoxicity of cancer stem‐like cells of HCT‐15 cells

“…Colonospheres show increased levels of total β‐catenin, cyclin‐D1, and c‐Myc, and upregulation of c‐Myc greatly enhances the formation of colonospheres . c‐Myc can upregulate and downregulate the expression of DR5 and c‐FLIP, respectively, and knockdown of the c‐Myc gene reduces the responsiveness to TRAIL and the expression of DR5 in PC3‐MM2 cells . Therefore, c‐Myc, which is required for properties of CSCs, may be responsible for hypersensitivity of HCT‐15 colony and CD44 + cells to TRAIL.…”

“…(35) c-Myc can upregulate and downregulate the expression of DR5 and c-FLIP, respectively, (25,26) and knockdown of the c-Myc gene reduces the responsiveness to TRAIL and the expression of DR5 in PC3-MM2 cells. (44) Therefore, c-Myc, which is required for properties of CSCs, may be responsible for hypersensitivity of HCT-15 colony and CD44 + cells to TRAIL. This hypothesis was supported by a previous report indicating that SP-cells with higher levels of c-Myc, which activates DR4 transcription, have a higher sensitivity to TRAIL than non-SP cells.…”

2′-Hydroxy-4-methylsulfonylchalcone enhances TRAIL-induced apoptosis in prostate cancer cells

“…The resistance of PC-3 cells can be in part explained by aneuploidy (more than 60 chromosomes), their complex form and great stability of their genome, and the huge variety in DNA repair machinery [48][49][50]. These elements could be blocked or inhibited by RG003 as it has been shown that the inhibition of the DNA repair machinery sensitizes cancer cells to apoptotic agents such as TRAIL [51,52].…”