Targeting mTOR by CZ415 Suppresses Cell Proliferation and Promotes Apoptosis via Lipin-1 in Cervical Cancer In Vitro and
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GYNECOLOGIC ONCOLOGY: ORIGINAL ARTICLE
Targeting mTOR by CZ415 Suppresses Cell Proliferation and Promotes Apoptosis via Lipin-1 in Cervical Cancer In Vitro and In Vivo Jinfeng Zhang 1 Received: 3 June 2020 / Accepted: 3 September 2020 # Society for Reproductive Investigation 2020
Abstract CZ415, a novel inhibitor of mammalian target of rapamycin (mTOR) kinase, has demonstrated anti-tumor activity in several types of cancer. However, its biological function and underlying mechanism of action in cervical cancer (CC) have not been fully studied. Two CC cell lines (Hela and Siha) were treated with increasing concentrations of CZ415. Cell viability was tested with the CCK-8 assay, cell proliferation was determined by Edu staining and the colony formation assay, and apoptosis was determined by flow cytometry and Hoechst 33342 staining. Protein expression was evaluated by western blotting. A nude mouse xenograft model was used to confirm the anti-tumor activity of CZ415 in vivo. Hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining were performed on samples of tumor tissue. Results showed that CZ415 inhibited CC cell survival in a dose- and time-dependent manner, and 100 nanomolar and 48 h were the optimal conditions. In vitro and in vivo experiments showed that treatment with CZ415 significantly inhibited spheroid formation, cell proliferation, and tumor growth. Further studies showed that the anti-cancer effects of CZ415 were due to an induction of apoptosis, which was accompanied by an upregulation of Bax and downregulation of Bcl-2 through Lipin-1. CZ415 also reduced the levels of mTOR/STAT3 expression. However, these phenotypic changes were reversed by overexpression of Lipin-1. Our results suggest that the novel mTOR inhibitor CZ415 mediates tumor malignancy via Lipin-1 and might be useful for treating CC. Keywords Cervical cancer . CZ415 . mTOR/STAT3 . Apoptosis
Introduction Cervical cancer (CC) is one of the most frequently diagnosed malignant gynecological tumors and the fourth leading cause of cancer-related death worldwide [1]. Approximately 500,000 new cases of CC are diagnosed each year worldwide and 250,000 patients die from the disease [2]. Although significant progress has been made in conventional surgical resection, chemotherapy, and radiotherapy, CC remains a significant public health concern and is associated with a poor 5Electronic supplementary material The online version of this article (https://doi.org/10.1007/s43032-020-00313-4) contains supplementary material, which is available to authorized users. * Jinfeng Zhang [email protected] 1
Department of Women’s Health Care, Xiaonan District Maternity and Child Healthcare Hospital, Xiaogan City 432000, Hubei Province, China
year survival rate [3, 4]. Therefore, it is critically important to develop new and effective targeted therapies for CC. Mammalian target of rapamycin (mTOR) is a protein kinase that consists of two multi-protein complexes, mTORC1 and mTORC2. In addition to the common constitute mTOR, the regulatory-associated pr
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