Anti‑cancer effects of the circadian clock modulating compound SR9009 in chordoma cell lines

Abstract

Originating from notochord remains, chordoma is a rare, chronic, low-grade axial skeletal cancer that is characterized by metastasis and adjacent tissue invasion, as well as a high risk of treatment resistance. Surgical intervention is the most common method used for treatment followed by radiotherapy to avoid the relapse of the tumor. Targeting the proteins involved in tumor-associated pathways is crucial since alternative drugs are required for the cure. The nuclear receptor REV-ERBα, a member of the circadian rhythm family, has elevated expression levels, which function as a tumor suppressor. SR9009 is a pyrrole-derived specific agonist that target REV-ERBα negatively regulates autophagy in cancer and induce apoptosis in a caspase-dependent manner and shown antitumor activity in several cancer models. Chordoma cells were treated with SR9009, and functional assays including colony formation, viability, and migration were tested. In addition, molecular docking analyses were performed to predict the interaction of SR9009 with proteins involved in migration, colony formation, proliferation were targeted. SR9009 reduced viability of chordoma cells in a concentration-dependent manner while sparing HNPCs, and 30 µM was selected as an effective concentration for subsequent experiments. At this concentration, SR9009 markedly inhibited chordoma cell migration and strongly suppressed colony formation in both CH22 and MUG-Chor1 cells. Molecular docking predicted high-affinity binding of SR9009 to PI3K, Akt1, Wnt3, β-catenin, and Nanog, suggesting potential interference with signaling networks implicated in chordoma cell proliferation and survival. Our findings indicate that SR9009 exerts robust anti-cancer effects in chordoma cell lines and highlight SR9009 as a promising candidate for further preclinical evaluation in chordoma. The involvement of circadian clock-related and associated signaling pathways in these effects remains putative and warrants mechanistic validation in future studies.