Quinacrine induces autophagy via the Dlg5/AKT pathway to inhibit osteosarcoma cell proliferation and suppresses migration and invasion through the Dlg5/Girdin pathway

Abstract

Background: Osteosarcoma (OS) is a malignant tumor of bone that originates from mesenchymal cells. Although improvements have been made in the survival rate of five years, the outlook for individuals with metastatic or recurrent disease remains unfavorable, highlighting the need for new therapeutic strategies and drug candidates. Quinacrine (QC) is a plant-derived bioactive compound extracted from the bark of the cinchona tree, has shown promising anticancer properties by suppressing the proliferation of cancer cells, inducing autophagy, and overcoming resistance to treatment. However, its potential therapeutic application in OS has yet to be thoroughly investigated.

Purpose: In this study, we investigated the inhibitory effects of QC, a plant-derived bioactive compound extracted from the bark of the cinchona tree, on the proliferation and migration of osteosarcoma cells and its potential mechanisms.

Methods: This study comprehensively evaluated the impact of QC on OS cells using both in vitro and in vivo models. Specific molecular pathways of OS cell growth inhibition by Quinacrine revealed by RNA-seq analysis. The inhibitory effect of QC on tumor growth and its potential organ toxicity were systematically investigated by constructing an in vivo mouse tumor model.

Results: The outcomes suggested that QC notably suppressed the growth, migration, and invasion of 143B and MG63 OS cells, causing the arrest of the cell cycle at the G2/M checkpoint. RNA sequencing analysis showed that QC inhibited AKT phosphorylation and induced autophagy in OS cells by increasing the expression of the Dlg5 gene. Furthermore, silencing the Dlg5 gene promoted OS cell proliferation and reduced the inhibitory effect of QC, thereby confirming the importance of Dlg5 in mediating its effects. This study also validated the molecular pathway by which QC inhibits OS cell migration and invasion by modulating the Dlg5/Girdin signaling pathway. In vivo, QC treatment led to a significant decrease in tumor growth in mice, with no evident organ toxicity observed.

Conclusion: In summary, QC suppresses the OS cells' growth by regulating the Dlg5/AKT signaling pathway and suppresses migration and invasion through the Dlg5/Girdin Pathway, emphasizing its potential as a therapeutic agent for OS.

Keywords: AKT signaling pathway; Autophagy; Dlg5; Osteosarcoma; Quinacrine.