Apoptosis by [Pt(O,O'-acac)(γ-acac)(DMS)] requires PKC-δ mediated p53 activation in malignant pleural mesothelioma
Antonella Muscella1, Carla Vetrugno1, Luca Giulio Cossa2
1Laboratory of Cell Pathology, Department of Biological and Environmental Sciences and Technologies (Di.S.Te.B.A.), University of Salento, Lecce, Italy.
Abstract:
Mesothelioma cancer cells have epithelioid or sarcomatoid morphology. The worst prognosis is associated with sarcomatoid phenotype and resistance to therapy is affected by cells heterogeneity. We recently showed that in ZL55 mesothelioma cell line of epithelioid origin [Pt(O,O'-acac)(γ-acac)(DMS)] (Ptac2S) has an antiproliferative effect in vitro and in vivo. Aim of this work was to extend the study on the effects of Ptac2S on ZL34 cell line, representative of sarcomatoid mesothelioma. ZL34 cells were used to assay the antitumor activity of Ptac2S in a mouse xenograft model in vivo. Then, both ZL34 and ZL55 cells were used in order to assess the involvement of p53 protein in (a) the processes underlying the sensitivity to chemotherapy and (b) the activation of various transduction proteins involved in apoptosis/survival processes. Ptac2S increases ZL34 cell death in vivo compared with cisplatin and, in vitro, Ptac2S was more efficacious than cisplatin in inducing apoptosis. In Ptac2S-treated ZL34 and ZL55 cells, p53 regulated gene products of apoptotic BAX and anti-apoptotic Bcl-2 proteins via transcriptional activation. Ptac2S activated PKC-δ and PKC-ε; their inhibition by PKC-siRNA decreased the apoptotic death of cells. PKC-δ was responsible for JNK1/2 activation that has a role in p53 activation. In addition, PKC-ε activation provoked phosphorylation of p38MAPK, concurring to apoptosis. In ZL34 cells, Ptac2S also activated PKC-α thus provoking ERK1/2 activation; inhibition of PKC-α, or ERK1/2, increased Ptac2S cytotoxicity. Results confirm that Ptac2S is a promising therapeutic agent for malignant mesothelioma, giving a substantial starting point for its further validation.
Insights
A novel platinum compound, Ptac2S, shows significant promise in treating malignant mesothelioma. It effectively induces cancer cell death and apoptosis, particularly in aggressive sarcomatoid types, offering a new therapeutic avenue.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Malignant mesothelioma exhibits epithelioid or sarcomatoid morphologies, with sarcomatoid types presenting a worse prognosis and therapeutic resistance.
- Cellular heterogeneity influences treatment outcomes in mesothelioma.
- Previous studies demonstrated the antiproliferative effects of Ptac2S in epithelioid mesothelioma cells (ZL55).
Purpose of the Study:
- To evaluate the efficacy of Ptac2S in sarcomatoid mesothelioma cells (ZL34).
- To investigate the role of p53 protein in Ptac2S-mediated chemotherapy sensitivity and apoptosis.
- To elucidate the involvement of various signal transduction proteins in Ptac2S-induced apoptosis and survival pathways.
Main Methods:
- Antitumor activity of Ptac2S was assessed in a ZL34 mouse xenograft model.
- In vitro studies utilized ZL34 and ZL55 cell lines to examine p53 involvement and apoptosis.
- Western blotting and siRNA techniques were employed to analyze protein activation and inhibition (PKC isoforms, JNK1/2, p38MAPK, ERK1/2, BAX, Bcl-2).
Main Results:
- Ptac2S demonstrated superior efficacy in increasing ZL34 cell death in vivo compared to cisplatin.
- In vitro, Ptac2S induced apoptosis more effectively than cisplatin in both ZL34 and ZL55 cells.
- Ptac2S modulated p53-regulated apoptotic (BAX) and anti-apoptotic (Bcl-2) proteins.
- Activation of PKC-δ, PKC-ε, and PKC-α by Ptac2S led to downstream activation of JNK1/2, p38MAPK, and ERK1/2, respectively, contributing to apoptosis.
- Inhibition of specific PKC isoforms or downstream kinases altered Ptac2S-induced cytotoxicity.
Conclusions:
- Ptac2S is a potent therapeutic agent against malignant mesothelioma, including the aggressive sarcomatoid subtype.
- The compound's mechanism involves p53-dependent regulation of apoptosis-related proteins and activation of specific protein kinase pathways.
- Ptac2S warrants further validation as a promising treatment for malignant mesothelioma.
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