PKC-δ/PKC-α activity balance regulates the lethal effects of cisplatin

Muscella, Antonella; Vetrugno, Carla; Antonaci, Giovanna; Cossa, Luca Giulio; Marsigliante, Santo

doi:10.1016/j.bcp.2015.08.103

Cited by 25 publications

(37 citation statements)

References 51 publications

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“…In the specific case of ZL-55, we have also shown that CDDP causes activation of the MAPK ERK1/2 [18]. In accordance with previous studies, Western blot analysis using specific antibodies to phosphorylated p38MAPK, revealed that Ptac2S provoked their phosphorylation, without altering the global level, as uncover by antibodies against un-phosphorylated form (Fig 5A).…”

Section: Resultssupporting

confidence: 89%

“…Between the isoforms expressed by cells ZL55, only two, the PKC-ε and the PKC-δ, showed a cytosol-to-membrane translocation; PKC-δ also translocated to the nuclear fraction (Fig 4A). Similarly to what happened with CDDP [18], the cells treated with Ptac2S also show the proteolytic activation of PKC-δ. While the full-length PKC-δ moved to the membrane and nuclei, its fragment was located to the mitochondria (Fig 4B and 4D).…”

Section: Resultsmentioning

confidence: 52%

“…Furthermore, PKC-δ–siRNA also inhibited the Ptac2S-provoked caspase-7 activation and PARP-1 cleavage (Fig 4F and 4G). Thus, the role of activated PKC-δ appears the same as the role it plays when the cells are incubated with CDDP [18]. …”

Section: Resultsmentioning

confidence: 99%

“…Using ZL55 mesothelioma cells, derived from an epithelial tumour biopsy of the pleural cavity of a 52-year old male, prior to treatment, with a known history of exposure to asbestos [23], we previously studied the cytotoxic effects of CDDP and highlighted the roles of PKC-δ and PKC-α: whilst PKC-δ is a pivotal portion of the apoptotic program, PKC-α mediates pro-survival effects [18]. In this paper we used a different Pt-based compound (Ptac2S) in order to determine its cytotoxicity and to unravel the cellular mechanisms, seeking comparisons with the previous study i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondrial membrane depolarization was detected by a shift in fluorescence emission of the lipophilic cationic probe 5,5’,6,6’-tetrachloro-1,1’,3,3’-tetraethylbenzimidazolo-carbocyanine iodide (JC-1), as described previously [18]. …”

Section: Methodsmentioning

confidence: 99%

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In Vitro and In Vivo Antitumor Activity of [Pt(O,O′-acac)(γ-acac)(DMS)] in Malignant Pleural Mesothelioma

Muscella¹,

Vetrugno²,

Cossa³

et al. 2016

PLoS ONE

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Malignant pleural mesothelioma (MPM) is an aggressive malignancy highly resistant to chemotherapy. There is an urgent need for effective therapy inasmuch as resistance, intrinsic and acquired, to conventional therapies is common. Among Pt(II) antitumor drugs, [Pt(O,O′-acac)(γ-acac)(DMS)] (Ptac2S) has recently attracted considerable attention due to its strong in vitro and in vivo antiproliferative activity and reduced toxicity. The purpose of this study was to examine the efficacy of Ptac2S treatment in MPM. We employed the ZL55 human mesothelioma cell line in vitro and in a murine xenograft model in vivo, to test the antitumor activity of Ptac2S. Cytotoxicity assays and Western blottings of different apoptosis and survival proteins were thus performed. Ptac2S increases MPM cell death in vitro and in vivo compared with cisplatin. Ptac2S was more efficacious than cisplatin also in inducing apoptosis characterized by: (a) mitochondria depolarization, (b) increase of bax expression and its cytosol-to-mitochondria translocation and decrease of Bcl-2 expression, (c) activation of caspase-7 and -9. Ptac2S activated full-length PKC-δ and generated a PKC-δ fragment. Full-length PKC-δ translocated to the nucleus and membrane, whilst PKC-δ fragment concentrated to mitochondria. Ptac2S was also responsible for the PKC-ε activation that provoked phosphorylation of p38. Both PKC-δ and PKC-ε inhibition (by PKC–siRNA) reduced the apoptotic death of ZL55 cells. Altogether, our results confirm that Ptac2S is a promising therapeutic agent for malignant mesothelioma, providing a solid starting point for its validation as a suitable candidate for further pharmacological testing.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 52%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

In Vitro and In Vivo Antitumor Activity of [Pt(O,O′-acac)(γ-acac)(DMS)] in Malignant Pleural Mesothelioma

Muscella¹,

Vetrugno²,

Cossa³

et al. 2016

PLoS ONE

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Inhibition of ZL55 cell proliferation by ADP via PKC‐dependent signalling pathway

Muscella

Cossa

Vetrugno

et al. 2017

Journal Cellular Physiology

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Extracellular nucleotides can regulate cell proliferation in both normal and tumorigenic tissues. Here, we studied how extracellular nucleotides regulate the proliferation of ZL55 cells, a mesothelioma-derived cell line obtained from bioptic samples of asbestos-exposed patients. ADP and 2-MeS-ADP inhibited ZL55 cell proliferation, whereas ATP, UTP, and UDP were inactive. The nucleotide potency profile and the blockade of the ADP-mediated inhibitory effect by the phospholipase C inhibitor U-73122 suggest that P2Y1 receptor controls ZL55 cell proliferation. The activation of P2Y1 receptor by ADP leads to activation of intracellular transduction pathways involving [Ca ] , PKC-δ/PKC-α, and MAPKs, ERK1/2 and JNK1/2. Cell treatment with ADP or 2-MeS-ADP also provokes the activation of p53, causing an accumulation of the G1 cyclin-dependent kinase inhibitors p21 and p27 . Inhibition of ZL55 cell proliferation by ADP was completely reversed by inhibiting MEK1/2, or JNK1/2, or PKC-δ, and PKC-α. Through the inhibition of ADP-activated transductional kinases it was found that PKC-δ was responsible for JNK1/2 activation. JNK1/2 has a role in transcriptional up-regulation of p53, p21 , and p27 . Conversely, the ADP-activated PKC-α provoked ERK1/2 phosphorylation. ERK1/2 increased p53 stabilization, required to G1 arrest of ZL55 cells. Concluding, the importance of the study is twofold: first, results shed light on the mechanism of cell cycle inhibition by ADP; second, results suggest that extracellular ADP may inhibit mesothelioma progression.

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ADP sensitizes ZL55 cells to the activity of cisplatin

Muscella

Cossa

Vetrugno

et al. 2018

Journal Cellular Physiology

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Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor in which cisplatin therapy is commonly used, although its effectiveness is limited. It follows that research efforts dedicated to identify promising combinations that can synergistically kill cancer cells are needed. Because we recently demonstrated that ADP inhibits the proliferation of ZL55 cells, an MPM-derived cell line obtained from bioptic samples of asbestos-exposed patients. Our objective in this study was to investigate the hypothesis that ADP also potentiates the cytotoxic activity of cisplatin. Results show that in ZL55 cells ADP enhanced (a) the cytotoxicity of cisplatin by 12-fold, (b) the restraint of cell clonogenic potential cisplatin-mediated, and (c) the number of apoptotic cells. Cisplatin, but not ADP, caused caspases activation; nevertheless, poly(ADP-ribose) polymerase-1 was not only cleaved in cisplatin-treated cells but also in cells treated with ADP alone. Furthermore, ADP, but not cisplatin, decreased mTOR and 6SK phosphorylations. Both ADP and cisplatin increased p53 protein, but ADP was also able to enhance p53 messenger RNA. P53 silencing resulted in a very large decrement of cell death induced by ADP or by cisplatin and reverted ADP effects on mTOR/S6K phosphorylation, suggesting that activated p53 may act as a negative regulator of mTOR. Consistently, the inhibition of mTOR by rapamycin also sensitized cells to cisplatin, and the effects of cisplatin plus rapamycin were identical to those obtained with cisplatin plus ADP. These findings suggest that the combination of ADP and cisplatin may be a promising strategy for the clinical treatment of cisplatin-resistant MPM.

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PKC-δ/PKC-α activity balance regulates the lethal effects of cisplatin

Cited by 25 publications

References 51 publications

In Vitro and In Vivo Antitumor Activity of [Pt(O,O′-acac)(γ-acac)(DMS)] in Malignant Pleural Mesothelioma

In Vitro and In Vivo Antitumor Activity of [Pt(O,O′-acac)(γ-acac)(DMS)] in Malignant Pleural Mesothelioma

Inhibition of ZL55 cell proliferation by ADP via PKC‐dependent signalling pathway

ADP sensitizes ZL55 cells to the activity of cisplatin

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