Daxx Shortens Mitotic Arrest Caused by Paclitaxel

Abstract

Resistance to the anti-neoplastic drug paclitaxel is frequent in breast cancer patients. Most studies of paclitaxel resistance have focused on pathways that elicit cellular response, while little is known about players involved in the acquirement of taxane resistance. By screening a cohort of breast cancer cell lines, we observed a correlation between level of protein Daxx and response to paclitaxel. Cells lines expressing increased level of Daxx displayed a robust paclitaxel response with nearly all cells undergoing micronucleation, while cell lines with low amount of Daxx showed a decrease in micronucleation, and accumulation in mitosis. At used paclitaxel concentrations, apoptotic levels were negligible in all cell lines tested. Human cell lines expressing anti-Daxx siRNA as well as Daxx-/- mouse fibroblasts showed similar cellular response to paclitaxel. Importantly, absence or depletion of Daxx resulted in cell survival after paclitaxel treatment, as measured by colony formation assay. We conclude that Daxx may be an important predictive factor in cellular response to paclitaxel, which emphasizes a critical but unknown function of this protein in mitotic progression, which, when disabled, leads to survival advantages upon paclitaxel treatment.

Regulation of c-met expression by transcription repressor Daxx

“…Recent report described HGF-induced repression of Daxx in breast epithelial cells (Leroy et al, 2006); thus, upregulation of c-met by HGF (Seol et al, 2000) may combine activation of c-met promoter by HGF and repression of Daxx. Daxx level was recently found as an important factor that determines proper response to the chemotherapeutic agent paclitaxel (Lindsay et al, 2007); thus, cells with low level of Daxx not only express increased c-met and are more metastatic-prompted, but also can be resistant to the taxol therapy.…”

USP7 and Daxx regulate mitosis progression and taxane sensitivity by affecting stability of Aurora-A kinase

“…We have previously shown that Daxx protein participates in mitosis regulation, thus affecting taxane resistance. 20,21 According to our model, 21 Daxx-deficient cells cannot resolve prometaphase/ metaphase transition as efficiently as control cells. This would explain the observation that, upon taxane treatment, cells with a low Daxx expression are protected from mitotic catastrophe/slippage and are able to complete mitosis and survive after taxane decay.…”

“…Therefore, experimental downregulation of USP7 reduced sensitivity to Taxol treatment in HEp2 cells, as previously shown for Daxx. 20,21 As Aurora-A overexpression correlates with poor patient outcome 43 and resistance to taxanes, 17 Aurora-A inhibitors have been developed for clinical application. Currently, MLN8054, a selective inhibitor of Aurora-A, 44 is in phase I clinical trials in patients with advanced malignancies and solid tumors including breast cancer.…”

“…10 Therefore, it is essential to identify predictive markers for chemotherapy selection, and to better understand mechanisms of taxane-induced cell death for rational development of novel targeted and combinatorial treatment to occur. We previously demonstrated that cells with low levels of Daxx have reduced sensitivity to taxanes 20,21 by persisting in a prometaphase block, escaping taxane-induced cell death. Daxx is a multifunctional protein that participates in physiological and pathological cellular processes, mostly via protein-protein interactions.…”

“…15,16 Aurora-A kinase has been linked to taxane resistance; 17 it is amplified in breast cancer, 18 overexpressed in several tumors with poor prognosis and it is an emerging therapeutic target. 19 Previously, we identified a novel role of death domainassociated protein (Daxx) in taxane sensitivity 20 and mitotic progression, 21 in both experimental models and breast cancer patients. Daxx is a highly conserved and developmentally essential nuclear protein, 22,23 involved in numerous cellular processes, such as transcriptional regulation, 22 apoptosis 24 and carcinogenesis.…”