Isoflurane promotes proliferation of squamous cervical cancer cells through mTOR-histone deacetylase 6 pathway
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Isoflurane promotes proliferation of squamous cervical cancer cells through mTOR‑histone deacetylase 6 pathway Wenwen Zhang1 · Fang Xue1 · Shangdan Xie1 · Cheng Chen1 · Jingwei Li1 · Xueqiong Zhu1 Received: 21 March 2020 / Accepted: 14 August 2020 © The Author(s) 2020
Abstract This study investigated the effect of isoflurane on the proliferation of squamous cervical cancer cells, with focus on histone deacetylase 6 that is closely related to carcinogenesis. Squamous cervical cancer cells SiHa and Caski were exposed to 1%, 2%, or 3% isoflurane for 2 h, respectively. Cell proliferation was measured with the cell counting kit (CCK-8) assay and determined by BrdU assay. Expression of histone deacetylase 6, phospho-AKT, phospho-mTOR, and proliferating cell nuclear antigen (PCNA) was assessed by Western blot. In order to block the histone deacetylase 6 (HDAC6) expression, siRNA transfection was performed. Isoflurane significantly promoted the proliferation of both SiHa and Caski cells, accompanied by upregulation of PCNA protein expression. Isoflurane increased the level of histone deacetylase 6 protein expression in both cells, and knockdown of histone deacetylase 6 attenuated the pro-proliferation effects of isoflurane. Additionally, activation of AKT/mTOR was found after isoflurane treatment, and mTOR inhibition abolished isoflurane-induced histone deacetylase 6 expression. However, inhibition of AKT phosphorylation had no effect on the expression of histone deacetylase 6 mediated by isoflurane. In conclusion, Isoflurane enhanced proliferation of cervical cancer cells through upregulation of histone deacetylase 6, which was associated with mTOR-dependent pathway, but not AKT-mediated pathway. Keyword Isoflurane · Proliferation · Histone deacetylase 6 · Cervical cancer · mTOR
Introduction Cervical cancer is the fourth most common cancer in women globally with 570,000 cases and 311,000 deaths estimated to occur in 2018, especially squamous cancer [1]. In spite of improvements in surgical techniques and radiation therapy for the management of cervical cancer, the prognosis remains poor. Emerging evidence has shown that perioperative factors including anesthesia technique and anesthetics may result in recurrence of cancer [2]. Limited data have demonstrated that the direct influence of anesthetics, especially inhalational ones on growth of tumor cells is contradictory [3–5]. A volatile anesthetic isoflurane is widely used
Wenwen Zhang and Fang Xue have contributed equally to this work. * Xueqiong Zhu [email protected] 1
Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou 325027, Zhejiang, China
for patients undergoing cervical cancer surgery. It was documented that isoflurane exerted anti-proliferative activity in pancreatic carcinoma, larynx cancer, and colon cancer cells in a time-dependent manner [3]. In contrast, it was found that isoflurane promoted the growth of renal cancer cells via hypoxia-inducible factor pathway [4]. Inc
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