Arborinine from Glycosmis parva leaf extract inhibits clear-cell renal cell carcinoma by inhibiting KDM1A/UBE2O signaling

Abstract

Background: Arborinine is a natural product isolated from Globigerina parva (G. parva) leaf extract that shows strong anticancer activity with its role in clear-cell renal cell carcinoma (ccRCC) unreported.
 Objective: We aim to evaluate the role of Arborinine in ccRCC.
 Design: Arborinine was tested for its effects in ccRCC cell lines in vitro and in silico.
 Results: Arborinine conferred inhibitory effect to ccRCC cells at reasonable doses. Arborinine showed inhibitory effects on Lysine Demethylase 1A (KDM1A) in ccRCC cells and decreased levels of KDM1A outputs and on epithelial mesenchymal transition (EMT) markers. Arborinine significantly inhibited proliferation, apoptosis, and cell cycle progression and migration of ccRCC cells. Using in silico ChIP analysis and luciferase activity validation, we identified Ubiquitin-conjugating enzyme E2O (UBE2O) as an active transcription target downstream of KDM1A. UBE2O expression was not only correlated with KDM1A expression but also associated with worsened prognosis in ccRCC. Overexpression of UBE2O abrogated cancer-inhibitory effect of Arborinine.
 Discussion: Arborinine holds promise as an additive in the treatment of ccRCC.
 Conclusions: We have shown for the first time that Arborinine showed inhibitory effect on ccRCC via KDM1A/UBE2O signaling.

Computational Pipeline to Identify Gene signatures that Define Cancer Subtypes

“…Upon further validation, these targets can lead to new treatment options for aggressive breast cancer subtypes such as Triple negative breast cancer. Similarly, many identified genes, such as KDM1A in astrocytoma, MMP3 (Bufu, et al, 2018) in glioblastoma, and PSEN1 in oligodendroglioma, have previously been correlated with cancer (Feng, et al, 2022; Xu, et al, 2018; Zhang, et al, 2022). These 3 genes also have inhibitors available, such as ladademstat, which can potentially target KDM1A (LSD1) (Salamero, et al, 2020), thus can be used to inhibit the growth of astrocytoma glioma.…”

Ruta angustifolia Pers. (Narrow-Leaved Fringed Rue): Pharmacological Properties and Phytochemical Profile

“…Recently, it was demonstrated that arborinine can block LSD1/KDM1A activity in clear-cell renal cell carcinoma ccRCC cell lines, sensitive or resistant to the kinase inhibitor sorafenib. In this case again, the compound blocked cell migration and invasion, cell cycle progression, and induced apoptosis [ 62 ]. A molecular modeling analysis suggested that arborinine could bind directly to the active site of LSD1, and blocks downstream signaling activities, notably the expression of the ubiquitin-conjugating enzyme E2O (UBE2O), an important protein for cancer cell survival and proliferation [ 62 ].…”

“…In this case again, the compound blocked cell migration and invasion, cell cycle progression, and induced apoptosis [ 62 ]. A molecular modeling analysis suggested that arborinine could bind directly to the active site of LSD1, and blocks downstream signaling activities, notably the expression of the ubiquitin-conjugating enzyme E2O (UBE2O), an important protein for cancer cell survival and proliferation [ 62 ]. The observation that arborinine represses LSD1/UBE2O signaling in ccRCC opens novel perspectives for research.…”