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

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.

Targeting CDK9: A novel biomarker in�the�treatment of endometrial cancer

“…The chemical inhibitors of CDK4/6, palbociclib, ribociclib and abemaciclib, have been used in multiple clinical trials worldwide to treat more than 30 different types of tumors, including endometrial cancer (38). A recent study demonstrated that increased expression of phosphorylated NPM/B23 (at Thr199) in cancer cells promotes its interaction with CDK6 and plays a key role in endometrial tumorigenesis (39). By inhibiting CDK4/6 kinase, palbociclib can inhibit the phosphorylation of NPM/B23 (Thr199) and promote the expression of estrogen receptor (ER)α, ultimately making hormone-refractory endometrial cancer sensitive to endocrine therapy (39).…”

“…A recent study demonstrated that increased expression of phosphorylated NPM/B23 (at Thr199) in cancer cells promotes its interaction with CDK6 and plays a key role in endometrial tumorigenesis (39). By inhibiting CDK4/6 kinase, palbociclib can inhibit the phosphorylation of NPM/B23 (Thr199) and promote the expression of estrogen receptor (ER)α, ultimately making hormone-refractory endometrial cancer sensitive to endocrine therapy (39). Yet, clinical trials of treatment with CDK9 inhibitors remain unsuccessful and involve many adverse effects (40).…”

A Patient-Derived Xenograft Model of Dedifferentiated Endometrial Carcinoma: A Proof-of-Concept Study for the Identification of New Molecularly Informed Treatment Approaches

“…IHC was performed as previously described [ 29 ]. Briefly, 4-μm-thick FFPE PDX-mLung, primary DEC, and lung metastasis specimens were deparaffinized in xylene and rehydrated through a series of graded ethanol washes in water.…”

Inhibition of BIRC2 Sensitizes α7-HPV-Related Cervical Squamous Cell Carcinoma to Chemotherapy

“…The Western blotting protocol was described in a previous study [34]. Briefly, cells were harvested, washed twice with PBS, and lysed in ice-cold RIPA lysis buffer.…”