The new InsP<inf>3</inf>Kinase inhibitor BIP-4 is competitive to InsP<inf>3</inf> and blocks proliferation and adhesion of lung cancer cells

© 2015 Elsevier Inc. All rights reserved. As ectopic expression of the neuronal inositol-1,4,5-trisphosphate-3-kinase A (InsP3Kinase) in tumor cells increases the metastatic potential, InsP3Kinase is an interesting target for tumor therapy. Recently, we have identified a membrane-permeable InsP3Kinase inhibitor (BAMB-4) exhibiting an IC50-value of 20 μM. Here we characterized a new InsP3Kinase inhibitor which shows a 130-fold lower IC50 value (157 ± 57 nM) as compared to BAMB-4. We demonstrate that this nitrophenolic compound, BIP-4, is non-competitive to ATP but competitive to InsP3, thus exhibits a high selectivity for inhibition of InsP3Kinase activity. Docking analysis suggested a putative binding mode of this molecule into the InsP3Kinase active site. Determination of cellular uptake in lung cancer cells (H1299) revealed that 6% of extracellular BIP-4 is internalized by non-endosomal uptake, showing that BIP-4 is not trapped inside endo/lysosomes but is available to inhibit cellular InsP3Kinase activity. Interestingly, we found that BIP-4 mediated inhibition of InsP3Kinase activity in the two lung cancer cell lines H1299 and LN4323 inhibited proliferation and adhesion at IC50 values of 3 μM or 2 μM, respectively. InsP3Kinase inhibition did not alter ATP-induced calcium signals but significantly reduced the level of Ins(1,3,4,5,6)P5. From these data we conclude that the inhibitory effect of BIP-4 on proliferation and adhesion of lung cancer cells does not result from alterations of calcium but from alterations of inositol phosphate signals. In summary, we reveal that inhibition of cellular InsP3Kinase by BIP-4 impairs proliferation and adhesion and therefore BIP-4 might be a promising compound to reduce the metastatic potential of lung carcinoma cells.Peer Reviewe

p53 and its isoforms in cancer

p53, p63 and p73 are members of the p53 gene family involved in development, differentiation and response to cellular stress. p53 gene is a transcription factor essential for the prevention of cancer formation. The p53 pathway is ubiquitously lost in human cancer either by p53 gene mutation (60% of cancers) or by lost of cell signalling upstream and downstream of p53 in the remaining cancers expressing WTp53 gene. As p53 pathway inactivation is a common denominator to all cancers, the understanding of p53 tumour suppressor activity is likely to bring us closer to cancer therapy. However, despite all the experimental evidences showing the importance of p53 in preventing carcinogenesis, it is difficult in clinical studies to link p53 status to cancer treatment and clinical outcome. The recent discovery that p53 gene encodes for nine different p53 proteins (isoforms) may have a profound impact on our understanding of p53 tumour suppressor activity. Studies in several tumour types have shown that the nine different p53 isoforms are abnormally expressed in tumour tissues compared to normal cells. p53 protein isoforms modulate p53 transcriptional activity and cell fate outcome in response to stress. Regulation of p53 function in normal and tumour tissues in man is likely to be more complex than has been hitherto appreciated. Therefore, the tumour p53 status needs to be determined more accurately by integrating p53 isoform expression, functional p53 mutation analysis and a panel of antibodies specific of p53 and of its target genes