Multifaceted Mechanisms of Cisplatin Resistance in Long-Term Treated Urothelial Carcinoma Cell Lines

Skowron, Margaretha A.; Melnikova, Margarita; Roermund, Joep G. H. van; Romano, Andrea; Albers, Peter; Thomale, Jürgen; Schulz, Wolfgang A.; Niegisch, Günter; Hoffmann, Michèle J.

doi:10.3390/ijms19020590

Cited by 28 publications

(27 citation statements)

References 50 publications

(69 reference statements)

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“…For MSTO-211H-cells, which showed a strong induction of MT2A expression, building up a protective barrier against cisplatin, the observed effect may be of profound clinical significance. Similar observations have been made in different tumor entities including renal carcinoma and urothelial carcinoma 24 , 25 .…”

Section: Discussionsupporting

confidence: 86%

Impact of metallothionein-knockdown on cisplatin resistance in malignant pleural mesothelioma

Borchert

Suckrau

Walter

et al. 2020

Sci Rep

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Malignant pleural mesothelioma (MPM) is a rare, but aggressive tumor with dismal prognosis. Platinum-based chemotherapy is regularly used as part of multimodality therapy. The expression of metallothioneins (MT) has been identified as a reason for cisplatin resistance, which often leads to early therapy failure or relapse. Thus, knockdown of MT expression may improve response to cisplatin treatment. The MT gene- and protein expression of the MPM-cell lines MSTO-211H, NCI-H2052 and NCI-H2452 and the human fibroblast cell line MRC-5, as well as their sensitivity to cisplatin treatment have been evaluated. Knockdown of MT1A, 1B and 2A expression was induced by RNA interference. MT expression was measured using quantitative real-time PCR. An in vitro Assay based on enzyme activity was used to detect cell viability, necrosis and apoptosis before and after incubation with cisplatin. MT2A gene expression could be detected in all MPM cell lines, showing the highest expression in NCI-H2452 and NCI-H2052, whereas gene expression levels of MT1A and MT1B were low or absent. The immunohistochemically protein expression of MT-I/II reflect MT2A gene expression levels. Especially for MSTO-211H cell presenting low initial MT2A levels, a strong induction of MT2A expression could be observed during cisplatin treatment, indicating a cell line-specific and platin-dependent adaption mechanism. Additionally, a MT2A-dependent cellular evasion of apoptosis during cisplatin could be observed, leading to three different MT based phenotypes. MSTO-211H cells showed lower apoptosis rates at an increased expression level of MT2A after cisplatin treatment (from sixfold to fourfold). NCI-H2052 cells showed no changes in MT2A expression, while apoptosis rate is the highest (8–12-fold). NCI-H2452 cells showed neither changes in alteration rate of MT2A expression nor changes in apoptosis rates, indicating an MT2A-independent resistance mechanism. Knockdown of MT2A expression levels resulted in significantly induced apoptotic rates during cisplatin treatment with strongest induction of apoptosis in each of the MPM cell lines, but in different markedness. A therapeutic meaningful effect of MT2A knockdown and subsequent cisplatin treatment could be observed in MSTO-211H cells. The present study showed MT2A to be part of the underlying mechanism of cisplatin resistance in MPM. Especially in MSTO-211H cells we could demonstrate major effects by knockdown of MT2A expression, verifying our hypothesis of an MT driven resistance mechanism. We could prove the inhibition of MT2A as a powerful tool to boost response rates to cisplatin-based therapy in vitro. These data carry the potential to enhance the clinical outcome and management of MPM in the future.

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Section: Discussionsupporting

confidence: 86%

Impact of metallothionein-knockdown on cisplatin resistance in malignant pleural mesothelioma

Borchert

Suckrau

Walter

et al. 2020

Sci Rep

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“…In previous work, these cell lines belonged to a set of four BC lines used to establish long-term Cisplatin-resistant sublines. Thus, we knew IC50 doses for cisplatin for various UCCs from previous work [ 22 ], and we chose RT-112 as a cell line with a high baseline IC50 (IC50 72 h 10 µM) and T-24 as one with a low baseline IC50 (IC50 72 h 2 µM). Overexpression following stable transfection was confirmed by RT-qPCR.…”

Section: Resultsmentioning

confidence: 99%

“…We then stably transfected two BC cell lines (RT-112 and T-24) with low MMP-7 expression, but we could not observe a significant change in their platinum sensitivity. This may be explained by the observation that cisplatin resistance may originate from a combination of various different factors [ 22 ]. Thus, in vitro manipulation of one factor alone may not be enough to reverse resistance, so that we cannot completely rule out from our data a functional impact of MMP-7.…”

Section: Discussionmentioning

confidence: 99%

MMP-7 Serum and Tissue Levels Are Associated with Poor Survival in Platinum-Treated Bladder Cancer Patients

et al. 2020

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Chemotherapy resistance is a main cause of therapeutic failure and death in bladder cancer. With the approval of immune checkpoint inhibitors, prediction of platinum treatment became of great clinical importance. Matrix metalloproteinase-7 (MMP-7) was shown to be involved in cisplatin resistance. Therefore, tissue and circulating MMP-7 levels were evaluated in 124 bladder cancer patients who received postoperative platinum-based chemotherapy. Tissue MMP-7 levels were analyzed by immunohistochemistry in 72 formalin-fixed, paraffin-embedded chemo-naïve tumor samples, while MMP-7 serum concentrations were determined in 132 serum samples of an independent cohort of 52 patients. MMP-7 tissue and serum levels were correlated with clinicopathological and follow-up data. MMP-7 gene expression was determined by RT-qPCR in 20 urothelial cancer cell lines and two non-malignant urothelial cell lines. MMP-7 was overexpressed in RT-112 and T-24 cells by stable transfection, to assess its functional involvement in platinum sensitivity. High MMP-7 tissue expression and pretreatment serum concentrations were independently associated with poor overall survival (tissue HR = 2.296, 95%CI = 1.235–4.268 and p = 0.009; serum HR = 2.743, 95%CI = 1.258–5.984 and p = 0.011). Therefore, MMP-7 tissue and serum analysis may help to optimize therapeutic decisions. Stable overexpression in RT-112 and T-24 cells did not affect platinum sensitivity.

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“…However, cisplatin can form multiple different adducts with nucleophilic residues and therefore affect multiple cellular pathways, and for this reason its exact mechanism of action remains unclear [ 9 , 10 ]. Therefore, cisplatin resistance mechanisms are complex and multifaceted, including an increased DNA repair capacity and anti-apoptotic ability, modifications in cellular transport and augmented anti-oxidative capacity [ 11 , 12 , 13 ]. Importantly, autophagy is another process which has been linked to the cisplatin resistance of cancer cells [ 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Prodigiosin Sensitizes Sensitive and Resistant Urothelial Carcinoma Cells to Cisplatin Treatment

et al. 2021

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Cisplatin-based treatment is the standard of care therapy for urothelial carcinomas. However, complex cisplatin resistance mechanisms limit the success of this approach. Both apoptosis and autophagy have been shown to contribute to this resistance. Prodigiosin, a secondary metabolite from various bacteria, exerts different biological activities including the modulation of these two cellular stress response pathways. We analyzed the effect of prodigiosin on protein levels of different autophagy- and apoptosis-related proteins in cisplatin-sensitive and -resistant urothelial carcinoma cells (UCCs). Furthermore, we investigated the effect on cell viability of prodigiosin alone or in combination with cisplatin. We made use of four different pairs of cisplatin-sensitive and -resistant UCCs. We found that prodigiosin blocked autophagy in UCCs and re-sensitized cisplatin-resistant cells to apoptotic cell death. Furthermore, we found that prodigiosin is a potent anticancer agent with nanomolar IC50 values in all tested UCCs. In combination studies, we observed that prodigiosin sensitized both cisplatin-sensitive and -resistant urothelial carcinoma cell lines to cisplatin treatment with synergistic effects in most tested cell lines. These effects of prodigiosin are at least partially mediated by altering lysosomal function, since we detected reduced activities of cathepsin B and L. We propose that prodigiosin is a promising candidate for the therapy of cisplatin-resistant urothelial carcinomas, either as a single agent or in combinatory therapeutic approaches.

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Multifaceted Mechanisms of Cisplatin Resistance in Long-Term Treated Urothelial Carcinoma Cell Lines

Cited by 28 publications

References 50 publications

Impact of metallothionein-knockdown on cisplatin resistance in malignant pleural mesothelioma

Impact of metallothionein-knockdown on cisplatin resistance in malignant pleural mesothelioma

MMP-7 Serum and Tissue Levels Are Associated with Poor Survival in Platinum-Treated Bladder Cancer Patients

Prodigiosin Sensitizes Sensitive and Resistant Urothelial Carcinoma Cells to Cisplatin Treatment

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