We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Oxysterol derivatives Oxy186 and Oxy210 inhibit WNT signaling in non-small cell lung cancer.
- Authors
Tang, Liu-Ya; Spezia, Marie; Chen, Ting; Shin, Jee-Hye; Wang, Feng; Stappenbeck, Frank; Lebensohn, Andres M.; Parhami, Farhad; Zhang, Ying E.
- Abstract
Background: Developmental signaling pathways such as those of Hedgehog (HH) and WNT play critical roles in cancer stem cell self-renewal, migration, and differentiation. They are often constitutively activated in many human malignancies, including non-small cell lung cancer (NSCLC). Previously, we reported that two oxysterol derivatives, Oxy186 and Oxy210, are potent inhibitors of HH/GLI signaling and NSCLC cancer cell growth. In addition, we also showed that Oxy210 is a potent inhibitor of TGF-β/SMAD signaling. In this follow-up study, we further explore the mechanism of action by which these oxysterols control NSCLC cell proliferation and tumor growth. Results: Using a GLI-responsive luciferase reporter assay, we show here that HH ligand could not mount a signaling response in the NSCLC cell line A549, even though Oxy186 and Oxy210 still inhibited non-canonical GLI activity and suppressed the proliferation of A549 cells. Further, we uncover an unexpected activity of these two oxysterols in inhibiting the WNT/β-catenin signaling at the level of LRP5/6 membrane receptors. We also show that in a subcutaneous xenograft tumor model generated from A549 cells, Oxy186, but not Oxy210, exhibits strong inhibition of tumor growth. Subsequent RNA-seq analysis of the xenograft tumor tissue reveal that the WNT/β-catenin pathway is the target of Oxy186 in vivo. Conclusion: The oxysterols Oxy186 and Oxy210 both possess inhibitory activity towards WNT/β-catenin signaling, and Oxy186 is also a potent inhibitor of NSCLC tumor growth.
- Subjects
WNT signal transduction; NON-small-cell lung carcinoma; CELL communication; CANCER cell growth; CANCER stem cells; TUMOR growth
- Publication
Cell & Bioscience, 2022, Vol 12, Issue 1, p1
- ISSN
2045-3701
- Publication type
Article
- DOI
10.1186/s13578-022-00857-9