Abstract
Platinum-based drugs remain as the cornerstone of cancer chemotherapy; however, development of multidrug resistance presents a therapeutic challenge. This study aims at understanding the molecular mechanisms underlying resistance to cisplatin and unraveling surrogate signaling networks that could revert sensitivity to apoptosis stimuli. We made use of three different sets of cell lines, A549 and H2030 non-small-cell lung cancer (NSCLC) and A2780 ovarian cancer cells and their cisplatin-resistant variants. Here we report that cisplatin-resistant cell lines displayed a multidrug-resistant phenotype. Changes in mitochondrial metabolism and defective mitochondrial signaling were unraveled in the resistant cells. More interestingly, a marked increase in sensitivity of the resistant cells to death receptor-induced apoptosis, in particular TRAIL (TNF-related apoptosis-inducing ligand)-mediated execution, was observed. Although this was not associated with an increase in gene transcription, a significant increase in the localization of TRAIL death receptor, DR4, to the lipid raft subdomains of plasma membrane was detected in the resistant variants. Furthermore, exposure of cisplatin-resistant cells to TRAIL resulted in upregulation of inducible nitric oxide synthase (iNOS) and increase in nitric oxide (NO) production that triggered the generation of peroxynitrite (ONOO−). Scavenging ONOO− rescued cells from TRAIL-induced apoptosis, thereby suggesting a critical role of ONOO− in TRAIL-induced execution of cisplatin-resistant cells. Notably, preincubation of cells with TRAIL restored sensitivity of resistant cells to cisplatin. These data provide compelling evidence for employing strategies to trigger death receptor signaling as a second-line treatment for cisplatin-resistant cancers.
Highlights
Platinum-based drugs form reactive intermediates that form DNA intra-strand crosslink adducts[1,6] that in turn activates DNA repair response
Received 15.4.15; revised 14.9.15; accepted 15.9.15; Edited by D Vucic content was analyzed by flow cytometry after staining with propidium iodide (PI); y axis: events, x axis: PI linear fluorescence, n = 3. (e) Wild-type A549 (WT), R1 and R2 cells were treated with the indicated doses of cisplatin for 24 h and caspase 3, 8 or 9 processing and PARP cleavage was determined by western blotting
Compared with the WT cells, R1 and R2 clones were relatively resistant to cisplatin (Figures 1a and c) and exhibited cross-resistance to another platinum-based compound, carboplatin (Figure 1b)
Summary
Platinum-based drugs form reactive intermediates that form DNA intra-strand crosslink adducts[1,6] that in turn activates DNA repair response. In panel c: * and ** indicate P-valueo0.05 compared to WT cells treated with cisplatin for 48 and 72 h, respectively machinery that allows cancer cell to evade genotoxic stress,[11] (2) increase in extrusion of platinum drugs via the expression of plasma membrane transporters[12,13,14] and (3) loss of p53 function and alterations in Bcl-2 family protein profiles that allow cancer cells to evade apoptosis.[15,16]. Despite the increased understanding of how tumor cells acquire resistance to platinum-based compounds, there are still limited second-line treatment options/strategies for patients who relapse and/or are refractory to conventional chemotherapeutics. The augmented sensitivity of cisplatin-resistant cells to TRAIL (TNF-related apoptosis-inducing ligand) signaling results from the redistribution of the death receptor 4 (DR4) to lipid raft subdomains within the plasma membrane. Our work highlights the potential of death receptor agonists, with TRAIL in particular, as a potential second-line chemotherapy for the treatment of recurrent/refractory malignancies
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