Highly expressed STAT1 contributes to the suppression of stemness properties in human paclitaxel-resistant ovarian cancer cells

Abstract

Signal transducer and activator of transcription-1 (STAT1) is an important factor in various cellular processes. The cancer stem cell (CSC) is considered as a tumor-initiating cell that drives the inner hierarchy in many cancers including epithelial ovarian cancer (EOC). Here, we explored for the first time the regulation of STAT1 on stemness properties in chemoresistant EOC cells. The paclitaxel (PTX)-resistant EOC cell line (OV3R-PTX) was derived from PTX-sensitive OVCAR-3 cells treated by the PTX regimen. A single cell clone OV3R-PTX-B4 was selected by fluorescence-activated cell sorting. PTX-resistant cells grew slowly in conventional 2D and 3D cultures, but tumor xenograft with PTX-resistant cells grew fast in nude mice. Interestingly, OV3R-PTX-B4 cells shared the characteristics of CSCs and stemness properties were found to be increased in the non-adherent spheroid culture system. The PTX-resistant cells had a high expression of CSC-related markers and low expression of STAT1 that had a high methylation level of CpG in its promoter region. Overexpressed STAT1 suppressed stemness properties, cell proliferation, and colony formation and favored the overall survival of patients with EOC. In summary, these data indicate a regulatory mechanism of STAT1 underlying drug resistance and provide a potential therapeutic application for EOC patients with PTX resistance.

Overexpressed COL5A1 is correlated with tumor progression, paclitaxel resistance, and tumor‐infiltrating immune cells in ovarian cancer

“…The human epithelial OC cell lines (OVCAR3, SKOV3, and A2780) and nontumorous human ovarian surface epithelial cells (HOSEpiC) were used as described previously (Zhang et al, 2017). The PTX‐resistant cells OV3R‐PTX and SK3R‐PTX were established in our laboratory (Wang et al, 2020). OVCAR3, A2780, and OV3R‐PTX cells were cultured in Roswell Park Memorial Institute‐1640 and SKOV3 and SK3R‐PTX cells were cultured in Dulbecco's modified Eagle medium (DMEM, 4.5 g/L glucose, Corning Inc.) with 10% fetal bovine serum (FBS, Invitrogen).…”

“…The PTX toxicity was detected using a CCK‐8 kit and cell resistance to PTX was measured by the half‐maximal inhibitory concentration (IC 50 ). Briefly, OV3R‐PTX cells were seeded in 96‐well plates at a density of 1 × 10 4 cells/well after COL5A1 knockdown for 24 h. The cells were then treated with different concentrations of PTX for 48 h. For the spheroid formation of cancer stem cells, the procedures were described previously (Wang et al, 2020).…”

The Dual Role of STAT1 in Ovarian Cancer: Insight Into Molecular Mechanisms and Application Potentials

“…Our group is first to demonstrate the involvement of STAT1 in stemness and paclitaxel-resistance in OC cells ( Wang et al, 2020 ). We have found that a clone of paclitaxel-resistant cells shares the characteristics of CSCs and has stemness properties.…”

“…Signal transducer and activator of transcription 1 has been reported to enhance anti-tumor immune response and is considered to inhibit tumor growth ( Avalle et al, 2012 ). However, during tumorigenesis, malignant cells avoid the above impairment through downregulating STAT1 by the methylation of STAT1 in its promoter; the low expression level of STAT1 is observed in a chemoresistant cell line ( Wang et al, 2020 ). Thus, more attention should be paid to the effects of STAT1 on the significance of the TME, the integration of various signals, and the nature of tumor cells.…”

<p>Effect of Starvation in Reversing Cancer Chemoresistance Based on Drug-Resistance Detection by Dextran Nanoparticles</p>

“…Human ovarian cancer cell line OVCAR-3 and human immortalized myelogenous leukemia cell line K562 were purchased from American Type Culture Collection (ATCC, Manassas, VA, USA). Human ovarian cancer PTX-resistant cell line OV3R-PTX referred to as DROV in the text was generated in this laboratory at Jinshan Hospital 32 and obtained a Chinese Invention Patent (# ZL201410708515.7). Human immortalized myelogenous leukemia doxorubicin (adriamycin, ADR)resistant cell line DRK562 was purchased from Keygen Biotech (Nanjing, China).…”