FBXL16 Promotes Endometrial Progesterone Resistance via PP2AB55α/Cyclin D1 Axis in Ishikawa

Abstract

Background. F-box proteins are essential components of the E3 ubiquitin ligases which are involved in the regulation of almost all life activities such as cell cycle, proliferation, and apoptosis, which have become an important research and drug target. However, there are few studies on F-box and leucine-rich repeat protein 16 (FBXL16) in endometrial carcinoma. Methods. Clinical samples were collected for determining the correlation between FBXL16 and endometrial carcinoma. Cells were screened and established with Ishikawa cells which proved the fundamental role of FBXL16 in regulating cell proliferation and cell cycle. The MPA-resistant endometrial carcinoma cell line Ishikawa/MPA was established. FBXL16, PP2AB55α, and cyclin D1 were analyzed separately in MPA sensitive and resistant Ishikawa cells in vitro and in vivo. Results. The high expression of FBXL16 was positively correlated with MPA resistance and poor prognosis of endometrial cancer. MPA tolerance of endometrial cancer cells was inhibited by knockdown of FBXL16 in DNA content assessment, CCK-8, and colony formation. It was confirmed that FBXL16 inhibited the activity of substrate PP2AB55α by binding to PP2A, reduced the phosphorylation level at Thr308 site of AKT1, inhibited the expression of GSK-3β, and thus led to a significant decrease in the phosphorylation level of cyclin D1, which prevented the ubiquitination recognition and degradation of cyclin D1. Conclusion. In our experiments, FBXL16 binds PP2A to promote the dephosphorylation of Thr286 site of cyclin D1 via AKT1/GSK3β/cyclin D1 pathway, which is required for resisting the ubiquitination degradation and enhances the MPA resistance of Ishikawa.

FBXL16 promotes cell growth and drug resistance in lung adenocarcinomas with KRAS mutation by stabilizing IRS1 and upregulating IRS1/AKT signaling

“…Through their F-box domains, F-box proteins usually form an SCF (SKP1-CUL1-F-box) complex to constitute an active E3 ubiquitin ligase in which the F-box protein recruits substrates for protein ubiquitination [9,10]. While FBXL16 did not show detectable interaction with CUL1 and may not form an active E3 ligase [11,12], recent studies have demonstrated that FBXL16 is involved in regulating the ubiquitination and stability of oncoproteins, such as MYC, SRC3, CYCLIN D1, and HIF1 alpha [13][14][15][16]. By upregulating MYC stability, FBXL16 promotes cancer cell growth and migration [13].…”