Abstract

Impairment of metastasis development is a critical target for cancer therapy. We recently reported that phospholipase Cγ1 (PLCγ1) is involved in regulation of motility and invasion of cancer cells and is required for metastasis development and progression. Experimental metastasis assays in nude mice revealed that inducible knockdown of PLCγ1 strongly inhibits development of MDA-MB-231-derived lung metastasis and reverts metastasis formation. In an effort to develop anti-metastatic drugs, different inositol phosphates compounds were tested to identify potential PLCγ1 inhibitors. We found that a synthetic derivative of inositol pentakisphosphate, Ins(1,3,4,5)P5, inhibits cell migration and 3D invasion in MDA-MB-231 and MDA-MB-435 human breast cancer cell lines and in TSA murine mammary adenocarcinoma cells and reduces calcium release upon EGF stimulation indicating a potential inhibition on PLCγ1 activity. Kinase profile assay, performed in vitro to test the potential inhibitory effect of the Ins(1,3,4,5)P5 synthetic derivative on different kinases showed a specific inhibition of the 3-phosphoinositide-dependent-protein kinase 1 (PDK1) with an IC50 of 26 nM. Knockdown of PDK1 using the small interfering RNA technology in breast cancer cell line MDA-MB-231 showed an impairment in cell migration and invasion and inhibition of EGF-induced calcium mobilisation. In addition, it has been recently shown that PDK1 is a critical determinant for resistance to tamoxifen anti-cancer drug. Our experiments show that combined treatment of the Ins(1,3,4,5)P5 synthetic derivative with tamoxifen, paclitaxel, and curcumin in MCF7 and MDA-MB-468 cells results in additive or more than additive effects, and therefore suggest that this novel PDK1 inhibitor can be potentially used in combination with other drugs to increase their anti-cancer activity.

Highlights

  • The response rarely sustains long among the responders for Herceptin monotherapy treatment

  • We have provided a novel mechanism of acquired resistance to Herceptin in human epidermal growth factor receptor 2 (HER2)-positive breast cancer and have resolved the inconsistencies in the literature regarding the effect of Herceptin on HER2 phosphorylation

  • Using a range of biochemical and cell-biology techniques, we have shown that BRCA1 is modified by SUMO in response to genotoxic stress, and co-localises at sites of DNA damage with SUMO1, SUMO2/3 and the SUMO conjugating enzyme Ubc9

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Summary

Introduction

The response rarely sustains long among the responders for Herceptin (trastuzumab) monotherapy treatment. BRCA1 is strongly implicated in the maintenance of genomic stability by its involvement in multiple cellular pathways including DNA damage signalling, DNA repair, cell cycle regulation, protein ubiquitination, chromatin remodelling, transcriptional regulation and apoptosis Both pathological and gene expression profiling studies provide evidence that breast cancers with germline mutations in BRCA1 are different from non-BRCA1-related breast cancers. The vitreous humour is one of the few tissues in the body that is avascular and virtually acellular, and previous studies have indicated that opticin contributes to the maintenance of this state by inhibition of angiogenesis The aim of this present study is to investigate the effect and mode of action of opticin in suppressing tumour cell proliferation and migration in vitro in a panel of breast cancer cell lines and to establish its therapeutic efficacy in human breast tumour xenografts in vivo. Using receptorselective ligands (patent filed by MRC Technology) specific for the TRAIL death receptors, TRAIL-R1/TRAIL-R2, we have previously shown that primary leukaemic cells isolated from patients with chronic lymphocytic leukaemia can be selectively sensitized to apoptosis by combining an a histone deacetylase inhibitor (HDACi) with a TRAIL-R1-specific form of TRAIL/TRAIL-R1 mAb

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