STAT3/IRF1 Pathway Activation Sensitizes Cervical Cancer Cells to Chemotherapeutic Drugs

Abstract

Neoadjuvant radio/chemotherapy regimens can markedly improve cervical cancer outcome in a subset of patients, while other patients show poor responses, but may encounter severe adverse effects. Thus, there is a strong need for predictive biomarkers to improve clinical management of cervical cancer patients. STAT3 is considered as a critical antiapoptotic factor in various malignancies. We therefore investigated STAT3 activation during cervical carcinogenesis and its impact on the response of cervical cancer cells to chemotherapeutic drugs. Tyr705-phosphorylated STAT3 increased from lowgrade cervical intraepithelial neoplasia (CIN1) to precancerous CIN3 lesions. Notably, pTyr705-STAT3 activation significantly declined from CIN3 to invasive cancer, also when compared in the same clinical biopsy. pTyr705-STAT3 was also low or absent in cultured human cervical cancer cell lines, consistent with the in vivo expression data. Unexpectedly, IL6-type cytokine signaling inducing STAT3 activation rendered cervical cancer cells significantly more susceptible to chemotherapeutic drugs, that is, cisplatin or etoposide. This chemosensitization was STAT3-dependent and we identified IFN regulatory factor-1 (IRF1) as the STAT3-inducible mediator required for cell death enhancement. In line with these data, pTyr705-STAT3 significantly correlated with nuclear IRF1 expression in cervical cancer in vivo. Importantly, high IRF1 expression in pretreatment cervical cancer biopsy cells was associated with a significantly better response to neoadjuvant radio/chemotherapy of the patients. In summary, our study has identified a key role of the STAT3/IRF1 pathway for chemosensitization in cervical cancer. Our results suggest that pretherapeutic IRF1 expression should be evaluated as a novel predictive biomarker for neoadjuvant radio/chemotherapy responses. Cancer Res; 76(13); 3872-83. Ó2016 AACR.

Sequential Interferon β-Cisplatin Treatment Enhances the Surface Exposure of Calreticulin in Cancer Cells via an Interferon Regulatory Factor 1-Dependent Manner

“…IRF was identified as a STAT3-inducible proapoptotic factor that mediated chemosensitization of cervical cancer cells by the pretreatment of a pleiotropic cytokine, oncostatin M [52]. In addition, IRF1 expression is associated with response to radio/chemotherapy in cervical cancer patients [52]. Similar to this study, we also found that sequential IFNβ-cisplatin treatment-induced IRF1 expression was responsible for the enhanced anticancer activity of cisplatin.…”

“…IRF1 has been considered a tumor suppressor [47][48][49][50][51]. IRF was identified as a STAT3-inducible proapoptotic factor that mediated chemosensitization of cervical cancer cells by the pretreatment of a pleiotropic cytokine, oncostatin M [52]. In addition, IRF1 expression is associated with response to radio/chemotherapy in cervical cancer patients [52].…”

Oncostatin M treatment increases the responsiveness toward cisplatin‑based chemoradiotherapy in cervical cancer cells in a STAT3‑dependent manner

“…We have recently shown that stimulation of cervical cancer cells with IL-6 in combination with the soluble IL-6R or OSM can potently activate STAT3 which leads to IRF1 up-regulation (10). Patients with high expression of the STAT3-regulated pro-apoptotic IRF1 in pretreatment cervical cancer biopsy cells showed in fact significantly higher responses to neoadjuvant chemoand chemoradiotherapy (10). In line with this, the in vitro results from this study confirmed that cell death sensitization toward irradiation or chemoradiotherapy is induced by OSM Table I.…”

“…We clarified the molecular mechanism responsible for cell death sensitization, which was dependent on the STAT3/IRF1 signaling pathway. This was unexpected because in cervical cancer patients in situ the STAT3 activation is weak or absent (10). This is in contrast to other malignancies, where STAT3 is constitutively active and is a considered anti-apoptotic factor (13)(14)(15).…”

“…We found that pre-treatment of cervical carcinoma cells with Oncostatin M (OSM) resulted in enhanced responsiveness of the cells to chemotherapeutic drugs (10). OSM is a member of the IL6-type cytokine family (11) and binds to the OSM receptor-b which then associates with the receptor chain gp130.…”