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  • Targeting MDMX and PKCδ to improve current uveal melanoma therapeutic strategies.

Targeting MDMX and PKCδ to improve current uveal melanoma therapeutic strategies.

Oncogenesis (2018-03-30)
R C Heijkants, M Nieveen, K C 't Hart, A F A S Teunisse, A G Jochemsen
ABSTRACT

Uveal melanoma (UM) is the most frequent ocular cancer in adults, accounting for ~5% of the total melanoma incidence. Although the primary tumor is well treatable, patients frequently develop metastases for which no curative therapy exists. Highly activated protein kinase C (PKC) is a common feature of UM and has shown potential as therapeutic intervention for UM patients. Unfortunately, PKC inhibition as single treatment appears to have only limited clinical benefit. Combining PKC inhibition with activation of p53, which is rarely mutated in UM, by MDM2 inhibitors has shown promising results in vitro and in vivo. However, clinical studies have shown strong adverse effects of MDM2 inhibition. Therefore, we investigated alternative approaches to achieve similar anticancer effects, but with potentially less adverse effects. We studied the potential of targeting MDMX, an essential p53 inhibitor during embryonal development but less universally expressed in adult tissues compared with MDM2. Therefore, targeting MDMX is predicted to have less adverse effects in patients. Depletion of MDMX, like the pharmacological activation of p53, inhibits the survival of UM cells, which is enhanced in combination with PKC inhibition. Also pan-PKC inhibitors elicit adverse effects in patients. As the PKC family consists of 10 different isoforms, it could be hypothesized that targeting a single PKC isoform would have less adverse effects compared with a pan-PKC inhibitor. Here we show that specifically depleting PKCδ inhibits UM cell growth, which can be further enhanced by p53 reactivation. In conclusion, our data show that the synergistic effects of p53 activation by MDM2 inhibition and broad spectrum PKC inhibition on survival of UM cells can also largely be achieved by the presumably less toxic combination of depletion of MDMX and targeting a specific PKC isoform, PKCδ.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal Anti-Vinculin antibody produced in mouse, clone hVIN-1, ascites fluid
Sigma-Aldrich
Anti-Vinculin Mouse mAb (V284 or VLN01), liquid, Calbiochem®, from mouse
Sigma-Aldrich
Anti-p21/WAF1/Cip1 Antibody, clone CP74, clone CP74, Upstate®, from mouse
Sigma-Aldrich
Anti-MDM2 Antibody, clone 3G9, clone 3G9, from mouse
Sigma-Aldrich
Anti-Mdmx Antibody, clone 8C6, clone 8C6, from mouse