Glycogen synthase kinase‐3β inactivation promotes cervical cancer progression, invasion, and drug resistance

Abstract Human papillomavirus (HPV) infection‐dependent cervical cancer is one of the most common gynecological cancers and often becomes aggressive, with rapid proliferation, invasion/migration, and drug resistance. Here, 135 fresh human cervical squamous cell carcinoma (CSCC) tissue specimens, comprising 21 adjacent normal (AN), 30 cervical intraepithelial neoplasia (CIN 1–3 ), 45 CSCC, and 39 drugs (chemo‐radiation)‐resistant cervical tumor (DRCT) tissues were included. HPV‐positive (HeLa, SiHa), HPV‐negative (C33A), and cisplatin‐resistant (CisR–HeLa/–SiHa/–C33A) cell lines were used for in vitro studies. HPV16/18 oncoproteins E6/E7, pERK1/2, and glycogen synthase kinase‐3 (GSK3) and the matrix metalloproteinases (MMPs) MMP‐9/‐2 were assessed using immunohistochemistry, WB, and gelatin zymography. HPV16/18 infection was observed in 16.7% of the CIN 1‐3 , 77.8% of the CSCC, and 89.7% of DRCT samples. Total and inactive GSK3β expressions were associated with overall CSCC progression ( p = 0.039 and p = 0.024, respectively) and chemoresistance ( p = 0.004 and p = 0.014, respectively). Positive correlations were observed, between the expression of E6 and pGSK3β expression ( p = 0.013); E6 and CSCC progression ( p < 0.0001)/drug resistance ( p = 0.0001). CisR–HeLa/–SiHa was more dependent on pGSK3β, and activation of GSK3 by SMIs (iAkt), treatment with nimbolide, or knockdown of E6/E7 reduced cisplatin resistance and promoted apoptosis. Hence, the activation of GSK3β with nimbolide and iAkt can be exploited for therapeutic interventions of cervical cancer.