Suppression of CYLD by HER3 confers ovarian cancer platinum resistance via inhibiting apoptosis and by inducing drug efflux.

Abstract

Background: Ovarian cancer (OC) is the most pathogenic gynecological malignant tumor in the world. Due to the difficulty of early diagnosis, most of patients developed chemo-resistance and recurrence during/after chemotherapy.

Methods: CCK8 and flow cytometry were utilized to assess drug sensitivity and apoptosis in parental and drug resistant cell lines. CYLD knockdown or overexpressed cells were employed to investigate its regulatory involvement in DDP resistance. Clinical tumor samples have been utilized to investigate the clinical relevance of CYLD. The drug synergistic effects were investigated through drug combination methods and a nude mice model with ABCB1 inhibitor or HER3 inhibitor.

Results: In this study, we found that CYLD levels were significantly reduced in DDP-resistant cancer tissues and cells compared to the normal tissues and cells. CYLD knockdown in DDP-sensitive cells was sufficient to converse the cells to become DDP resistant by reducing cell apoptosis through increasing Bcl-XL and inhibiting Bax, and by increasing drug efflux via upregulating ABCB1 expression. HER3 expression levels were substantially higher in resistant cancer tissues and cells, and HER3 was the upstream facilitator of suppressing CYLD expression via STAT3 signaling. Furthermore, overexpression of CYLD in resistant cells increased sensitivity to platinum-based chemotherapy both in vitro and in vivo. ABCB1 was a key downstream target of CYLD for regulating tumor growth and therapeutic resistance both in vitro and in vivo, CYLD knockdown promoted the translocation of p65 to nucleus which increased ABCB1 expression through transcriptional activation. High expression levels of HER3 rendered CYLD suppression, consequently, mediated DDP resistance by blocking cell apoptosis pathways and promoting the drug efflux in ovarian cancer.

Conclusions: Our findings identify novel HER3/CYLD/ABCB1 axis that regulate tumor growth and DDP resistance, which may be used as potential novel therapeutic target(s) to overcome ovarian cancer DDP resistance.