Bazedoxifene, a GP130 Inhibitor, Modulates EMT Signaling and Exhibits Antitumor Effects in HPV-Positive Cervical Cancer.

Leekyung Kim,Tae-Hwe Heo,Hyemin Park,Sun-Ae Park,Heejung Kim

doi:10.3390/ijms22168693

Leekyung Kim, Tae-Hwe Heo + Show 3 more

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https://doi.org/10.3390/ijms22168693

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Abstract

Persistent HPV (Human Papillomavirus) infection is the primary cause of cervical cancer. Despite the development of the HPV vaccine to prevent infections, cervical cancer is still a fatal malignant tumor and metastatic disease, and it is often difficult to treat, so a new treatment strategy is needed. The FDA-approved drug Bazedoxifene is a novel inhibitor of protein–protein interactions between IL-6 and GP130. Multiple ligand simultaneous docking and drug repositioning approaches have demonstrated that an IL-6/GP130 inhibitor can act as a selective estrogen modulator. However, the molecular basis for GP130 activation in cervical cancer remains unclear. In this study, we investigated the anticancer properties of Bazedoxifene in HPV-positive cervical cancer cells. In vitro and in vivo experiments showed that Bazedoxifene inhibited cell invasion, migration, colony formation, and tumor growth in cervical cancer cells. We also confirmed that Bazedoxifene inhibits the GP130/STAT3 pathway and suppresses the EMT (Epithelial-mesenchymal transition) sub-signal. Thus, these data not only suggest a molecular mechanism by which the GP130/STAT3 pathway may promote cancer, but also may provide a basis for cervical cancer replacement therapy.

Highlights

Hyung Sik KimCervical cancer is the fourth most common cancer and second most common gynecological cancer in the global female population [1,2,3]
Several studies have investigated the ability of IL-6/GP130 to promote chemotherapy resistance in several cancers as IL-6 is known to bind to the extracellular surface receptor glycoprotein 130 (GP130) and activate cell survival-related pathways [7,8,9]
We suggest that Bazedoxifene is a potent inhibitor of GP130/STAT3 signaling in HPV-positive cervical cancer cells

Summary

Introduction

Hyung Sik KimCervical cancer is the fourth most common cancer and second most common gynecological cancer in the global female population [1,2,3]. IL-6 plays a role in recruiting immune cells within the tumor microenvironment and stimulates the production of pro-inflammatory cytokines. It is involved in the pathogenesis of several chronic inflammatory diseases and promote the development and progression of tumors. IL-6 can be expressed at high levels in the tumor microenvironment and is a major mediator of inflammation. IL-6 can directly stimulate the proliferation, survival, and invasiveness of tumor cells. Several studies have investigated the ability of IL-6/GP130 to promote chemotherapy resistance in several cancers as IL-6 is known to bind to the extracellular surface receptor glycoprotein 130 (GP130) and activate cell survival-related pathways [7,8,9].

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