Regulation and reversal of paclitaxel resistance via the STAT1‑mediated apoptotic pathway in ovarian cancer

Ovarian cancer (OC) is the most lethal disease in women. Resistance to paclitaxel (PTX) is the main cause of treatment failure in patients with OC. The STAT1 protein is a transcription factor implicated in a variety of cellular processes. The present study explored the function and regulatory mechanism of STAT1 in the reversal of PTX resistance <i>in vivo</i> and <i>in vitro</i>. The OC cell lines SK‑OV‑3 and OVCAR‑3 and their counterpart PTX‑resistant OC cell lines SK3R‑PTX and OV3R‑PTX were applied. The Tet‑On STAT1‑overexpression plasmids were constructed using the technique of the Tet‑On gene expression system and were packaged by lentivirus. RNA and protein were detected by reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analysis, respectively. OC cell mRNA‑sequencing and subsequent RT‑qPCR verification revealed that STAT1 expression was downregulated in PTX‑resistant cells compared with their sensitive counterparts (P<0.01), except for STAT1β expression in SK3R cells (P>0.05). Cell viability was assessed using a CCK‑8 assay and PTX sensitivity was detected based on their IC₅₀ values. Overexpression of STAT1 sensitized PTX responses and decreased the tumor volume in xenograft mice. Bioinformatics analysis indicated that STAT1 had favorable effects on the overall survival of patients with OC. Apoptotic cells were detected using flow cytometry. STAT1α overexpression increased the percentage of apoptotic cells to 53.20±0.92 and 36.74±0.77% in OV3R‑PTX and A2780‑PTX cells, respectively, after 1 µM PTX treatment for 24 h. Mechanistically, overexpression of STAT1, especially STAT1α, confirmed by western blot and immunofluorescence staining, induced apoptosis by increasing apoptotic molecules such as Fas cell surface death receptor (FAS) and caspase‑8 (CASP8), which was abolished in the presence of a caspase blocker (Z‑VAD‑FMK). Furthermore, the dual‑luciferase assay confirmed that STAT1 directly bound to the promoter regions of the FAS and CASP8 genes. Thus, the present data demonstrated that STAT1 was a key mediator of the PTX chemotherapy response. Low STAT1 expression was a marker of PTX resistance, whereas overexpression of STAT1 sensitized OC cells to PTX and promoted apoptosis via the FAS/CASP8 signaling pathway. These findings may provide a potential therapeutic strategy to reverse PTX resistance in OC patients by targeting STAT1.