Tamoxifen is a putative substrate that affect the ubiquitin-proteasome pathway to the therapy of breast cancer

Milad Rouhimoghadam,1,* Shahrokh safarian,2 Jason s. carroll,3

1. Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Iran
2. Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Iran
3. Cancer Research UK, University of Cambridge, UK

Abstract

Introduction

Tamoxifen, a synthetic triphenyl-ethylene compound, is a member of a class of anticancer drugs known as selective estrogen receptor modulators. function of the ubiquitin-proteasome pathway is essential for many fundamental cellular processes, including the regulation of receptor signaling pathways, antigen processing, angiogenesis, apoptosis and for processing and degradation of misfolded and short-lived regulatory proteins such as transcription factors. this pathway has been validated as a target for antineoplastic therapy using both in vitro and preclinical models of human malignancies, and is influenced as part of the mechanism of action of certain chemotherapeutic agents.

Methods

Mcf-7 cells were treated with 250µm tamoxifen for 48 hours. total rna was extracted from the cells using tripure isolation reagent (roche diagnostics gmbh, germany) according to the kit’s protocol. following rna isolation, creation of an rna-seq library is the next step in transcriptome sequencing. in total, four cdna paired-end libraries were generated for transcriptome sequencing on illumina hiseq 2000 platform.

Results

The obtained raw data were subjected to the gene ontology (go) classification for pathway analysis of the screened degs. go functional enrichment analysis showed that 48 identified overexpressed genes belonged to the positive regulation of protein ubiquitination pathway (go:0031398). in addition to positive-regulation-of-protein-ubiquitination pathway (go:0031398), the ubiquitin-dependent-protein-catabolic process (go:0006511) and protein poly-ubiquitination pathway (go:0000209) play an active role in accelerating of ubiquitination pathways.

Conclusion

Protein degradation through the ubiquitin‐dependent proteasomal pathway has been implicated in cellular protein destruction. the ubiquitin-proteasome pathway is just beginning to be exploited as a target for cancer therapy. in this study, we demonstrate that tamoxifen as a nonsteroidal antiestrogen is able to activate ubiquitin-proteasome pathway.

Keywords

Tamoxifen, ubiquitin, breast cancer, proteasome