Piperlongumine Targets BIRC5 to Suppress Oral Squamous Cell Carcinoma: An Integrated Computational and Experimental Study

Abstract

Oral squamous cell carcinoma (OSCC) is still a major clinical problem and need an effective and selective therapeutic agent. Piperlongumine (PIP), a bioactive alkaloid of Piper longum, has been shown to have anticancer activity in OSCC, although molecular targets and mechanisms are still not known completely. In this study, an integrated bioinformatics, computational and experimental approaches were used to investigate the anti-cancer potential of PIP. Common OSCC-associated DEGs were detected from three OSCC gene expression datasets, and protein-protein interaction and functional enrichment analyses were subsequently performed. The PIP-related targets were prioritized using molecular docking, molecular dynamics simulation, MM/PBSA, free-energy landscape, and ADMET analyses. The findings were then confirmed with 2D and 3D culture of SCC9 and H357 tumor cells. Among the 444 OSCC-associated DEGs, BIRC5, CDK1, BUB1, BIRC5, and KIF23 were determined as hub genes of which all except MAD2L1 were linked to poor patient survival. MD simulation and MM/PBSA showed that BIRC5 has a stable free-energy landscape and favourable binding energy (-102.938 ± 5.488 kJ/mol). PIP selectively suppressed OSCC growth, enhanced ROS production, reduced MMP led to DNA damage, G2/M arrest and apoptosis, and down-regulated the expression of hub-gene, suggesting BIRC5 as a potential molecular target.