Abstract
We previously showed that [Pt(O,O’-acac)(γ-acac)(DMS)] ([Pt(acac)2(DMS)]) exerted substantial cytotoxic effects in SH-SY5Y neuroblastoma cells, and decreased metalloproteases (MMPs) production and cells migration in MCF-7 breast cancer cells. The ubiquitously distributed sodium-hydrogen antiporter 1 (NHE1) is involved in motility and invasion of many solid tumours. The present study focuses on the effects of [Pt(acac)2(DMS)] in SH-SY5Y cell migration and also on the possibility that NHE1 may be involved in such effect. After sublethal [Pt(acac)2(DMS)] treatment cell migration was examined by wounding assay and cell invasion by transwell assay. NHE1 activity was measured in BCECF-loaded SH-SY5Y as the rate of Na+-dependent intracellular pH recovery in response to an acute acid pulse. Gelatin zymography for MMP-2/9 activities, Western blottings of MMPs, MAPKs, mTOR, S6 and PKCs and small interfering RNAs to PKC-ε/-δ mRNA were performed. Sublethal concentrations of [Pt(acac)2(DMS)] decreases NHE1 activity, inhibites cell migration and invasion and decreases expression and activity of MMP-2 and -9. [Pt(acac)2(DMS)] administered to SH-SY5Y cells provokes the increment of ROS, generated by NADPH oxidase, responsible for the PKC-ε and PKC-δ activation. Whilst PKC-δ activates p38/MAPK, responsible for the inhibition of MMP-2 and -9 secretion, PKC-ε activates a pathway made of ERK1/2, mTOR and S6K responsible for the inhibition of NHE1 activity and cell migration. In conclusion, we have shown a drastic impairment in tumour cell metastatization in response to inhibition of NHE1 and MMPs activities by [Pt(acac)2(DMS)] occurring through a novel mechanism mediated by PKC-δ/-ε activation.
Highlights
Neuroblastoma is the most common tumor among children under 1 year of age and is prone to early metastasis; in 60–70% of neuroblastoma cases, systemic organ or bone marrow metastasis is detected at presentation and is the leading cause of death in these patients
We previously showed that ROS generated by NADPH oxidase was responsible for the [Pt(acac)2(DMS)]-mediated PKC-d and -e activation and consequential phosphorylation of p38MAPK and ERK1/2 [24]
The tumor acidic microenvironment exerts profound influence on cancer cell invasion and metastasis and these characteristics are considered as important targets for the development of new anticancer therapies
Summary
Neuroblastoma is the most common tumor among children under 1 year of age and is prone to early metastasis; in 60–70% of neuroblastoma cases, systemic organ or bone marrow metastasis is detected at presentation and is the leading cause of death in these patients. Recent work demonstrated that in these complexes substitution of the sulphur ligand with the much more inert ammonia gave almost the same in vitro cytotoxicity results on cisplatin resistant MCF-7 cells, an activity based on some molecular recognition mechanism may be involved [22] The ability of this compound to induce apoptosis in human cancer cells has been studied and compared to cisplatin. ERK1/2 activation has been demonstrated to regulate the Na+/H+ exchange, either positively [29] or negatively [30] and [31]; the role of p70RSK in the regulation of NHE1 is beginning to be understood, but its implication in cell migration and invasion need to be further evaluated Another purpose of the present study was to investigate the diverse intracellular pathways involved in the regulation of Na+/H+ exchange, migration and invasion after [Pt(acac)2(DMS)] administration. Our results provide new insights into the relationship between NHE1 and metastatic process, and demonstrate that activation of ERK is a critical component of the signaling pathway through which [Pt(acac)2(DMS)] inhibits Na+/H+ exchange
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