Palbociclib Promotes Dephosphorylation of NPM/B23 at Threonine 199 and Inhibits Endometrial Cancer Cell Growth.

Chiao-Yun Lin,Chia-Lung Tsai,Chyong-Huey Lai,Li-Yu Lee,Tzu-Hao Wang,Angel Chao,Cheng-Lung Hsu

doi:10.3390/cancers11071025

Chiao-Yun Lin, Chia-Lung Tsai + Show 5 more

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https://doi.org/10.3390/cancers11071025

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Abstract

Endometrial cancer incidence rates are growing, especially in countries with rapid socioeconomic transitions. Despite recent advances in chemotherapy, hormone therapy, and targeted therapy, advanced/recurrent disease remains a clinical challenge. Palbociclib—a selective inhibitor of cyclin-dependent kinases (CDK) 4/6—has therapeutic potential against estrogen receptor (ER)-positive and HER2-negative breast cancer. However, the question as to whether it can be clinically useful in endometrial cancer remains open. Here, we show that combined treatment with palbociclib and megesterol acetate exerts synergistic antiproliferative effects against endometrial cancer cells. Treatment of cancer cells with palbociclib suppressed NPM/B23 phosphorylation at threonine 199 (Thr199). We further demonstrated that CDK6 acts as a NPM/B23 kinase. Palbociclib-induced NPM/B23 dephosphorylation sensitized endometrial cancer cells to megesterol acetate through the upregulation of ERα expression. Immunohistochemistry revealed an overexpression of phospho-NPM/B23 (Thr199) in human endometrial cancer, and phospho-NPM/B23 (Thr199) expression levels were inversely associated with Erα in clinical specimen. In a xenograft tumor model, the combination of palbociclib and megesterol acetate successfully inhibited tumor growth. Taken together, our data indicate that palbociclib promoted NPM/B23 dephosphorylation at Thr199—an effect mediated by disruption of CDK6 kinase activity. We conclude that palbociclib holds promise for the treatment of endometrial cancer when used in combination with megesterol acetate.

Highlights

Endometrial cancer is the sixth most common gynecologic cancer worldwide and its incidence rate is growing—especially in countries with rapid socioeconomic transitions [1]
We have demonstrated that NPM/B23 silencing via AP2γ may activate ERα expression in endometrial cancer cells [26]
Because palbociclib is a selective inhibitor of cyclin-dependent kinases CDK4 and CDK6 and NPM/B23 can be phosphorylated either by CDK4 [14] or CDK6 [15], we tested whether this drug was able to inhibit NPM/B23 phosphorylation at several sites

Summary

Introduction

Endometrial cancer is the sixth most common gynecologic cancer worldwide and its incidence rate is growing—especially in countries with rapid socioeconomic transitions [1]. Hysterectomy remains the mainstay of definitive therapy [3], adjuvant chemo- and/or radio-therapy may confer a survival benefit in patients who are at high risk for recurrences or presenting with advanced disease. Cancers 2019, 11, 1025 advanced/recurrent disease is still challenging and the role of chemotherapy, hormone therapy, and targeted therapy remains under scrutiny. Endometrial cancers generally express estrogen and progesterone receptors [4]. The single best predictor of response was ER, which was significantly associated with clinical response and survival [6]. A reduced expression of ER has been associated with poor differentiation, advanced-stage tumors, disease recurrence, and adverse outcomes [7]. The disappearance of hormonal receptor expression is common in patients with recurrent estrogen-associated cancers [8]. It is critical to find new therapeutic targets that can restore functional hormones through either PR or ER, which sensitize to hormone therapy

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