The Role of TRIP6, ABCC3 and CPS1 Expression in Resistance of Ovarian Cancer to Taxanes.

Michael Jelinek,Iveta Voleska,Kamila Balusikova,Radka Vaclavikova,Jan Kovar,Karolina Seborova,Lukas Rob,Iwao Ojima,Changwei Wang,Alzbeta Kloudova-Spalenkova,Marcela Mrhalova,Petr Holy,Kamila Koucka,Pavel Soucek,Petr Daniel,Marie Ehrlichova,Martin Hruda

doi:10.3390/ijms23010073

Abstract

The main problem precluding successful therapy with conventional taxanes is de novo or acquired resistance to taxanes. Therefore, novel experimental taxane derivatives (Stony Brook taxanes; SB-Ts) are synthesized and tested as potential drugs against resistant solid tumors. Recently, we reported alterations in ABCC3, CPS1, and TRIP6 gene expression in a breast cancer cell line resistant to paclitaxel. The present study aimed to investigate gene expression changes of these three candidate molecules in the highly resistant ovarian carcinoma cells in vitro and corresponding in vivo models treated with paclitaxel and new experimental Stony Brook taxanes of the third generation (SB-T-121605 and SB-T-121606). We also addressed their prognostic meaning in ovarian carcinoma patients treated with taxanes. We estimated and observed changes in mRNA and protein profiles of ABCC3, CPS1, and TRIP6 in resistant and sensitive ovarian cancer cells and after the treatment of resistant ovarian cancer models with paclitaxel and Stony Brook taxanes in vitro and in vivo. Combining Stony Brook taxanes with paclitaxel caused downregulation of CPS1 in the paclitaxel-resistant mouse xenograft tumor model in vivo. Moreover, CPS1 overexpression seems to play a role of a prognostic biomarker of epithelial ovarian carcinoma patients’ poor survival. ABCC3 was overexpressed in EOC tumors, but after the treatment with taxanes, its up-regulation disappeared. Based on our results, we can suggest ABCC3 and CPS1 for further investigations as potential therapeutic targets in human cancers.

Highlights

Ovarian cancer is the seventh most common cancer in women worldwide, with around240,000 new cases per year [1]
It is not known whether deregulation of ABCC3, CPS1 and TRIP6 occurs in different types of paclitaxel-resistant ovarian carcinoma cells or how the deregulation is affected by the action of paclitaxel and novel taxane derivatives
There was no association between mRNA expression of ABCC3, CPS1, and TRIP6 and pathological data, the prognosis of we found a suggestive association of CPS1 mRNA expression with time to progression (TTP) of epithelial ovarian carcinomas (EOCs) patients

Summary

Introduction

Ovarian cancer is the seventh most common cancer in women worldwide, with around. 240,000 new cases per year [1]. Mitochondria play an essential role in apoptosis regulation, and they are essenRegarding the third candidate molecule, it signaling was reported that One. TRIP6, a zyxin family tial for cell metabolism and respiration, and cell of the mitochonmember being enriched at focal adhesions [43], has been markedly upregulated in paclitaxeldrial proteins, a urea cycle enzyme carbamoyl-phosphate synthetase I (CPS1), is signifiresistant breast cancer. It is not known whether deregulation of ABCC3, CPS1 and TRIP6 occurs in different types of paclitaxel-resistant ovarian carcinoma cells or how the deregulation is affected by the action of paclitaxel and novel taxane derivatives. The goal of this study was to assess whether ABCC3, CPS1, and TRIP6 might serve as biomarkers of prognosis, therapeutic response, and survival of ovarian carcinoma patients for improving therapy personalization

Results

Patients Characteristics

Samples from 89

Discussion

Materials

Cells and Culture Conditions

Cell Line Treatment with Paclitaxel and Novel Stony Brook Taxanes

Xenografts

In Vivo Treatment with Paclitaxel and Novel Stony Brook Taxanes

Patients Cohort Study

Isolation of Nucleic Acids and cDNA Synthesis

Quantitative Real-Time PCR