Paxillin promotes the invasion and migration of polyploid giant cancer cells with daughter cells after arsenic trioxide treatment by regulating the expression of cathepsin B/D.

Polyploid giant cancer cells (PGCCs) play an important role in regulating heterogeneity, growth, and chemotherapy resistance of malignant tumors. Paxillin is a unique cytoskeletal protein and drives persistent migration. In this study, we investigated the molecular mechanism by which paxillin regulates the invasion and migration of PGCCs with daughter cells (PDCs). We treated HCT116 and LoVo cells with arsenic trioxide (ATO) to induce the formation of PGCCs, and the migration, invasion, and proliferation abilities of PDCs were measured using wound-healing, western blot, immunofluorescence, cell transfection, and dequenching (DQ)-gelatin assays. ATO-induced PDCs had higher invasion, migration, and proliferation ability. Focal adhesion protein paxillin, cytoskeletal protein CDC42, and protease-related protein cathepsin B/D were highly expressed in PDCs. CDC42 promotes the phosphorylation of paxillin by regulating the expression of integrin β1. When phosphorylated at specific tyrosine residues, paxillin plays an important scaffold role in cell adhesion by recruiting structural and signaling molecules (cathepsin B/D) involved in cell movement and migration. Cathepsin B/D can also promote the phosphorylation of paxillin and FAK and promote the invasion and migration of PDCs by degrading the extracellular matrix and inducing cytoskeleton disorders. Paxillin phosphorylation plays an important role in PDCs invasion and migration. Paxillin may be a potential predictor of metastasis and an independent prognostic factor for recurrence and may target phosphorylation to mitigate the impact of chemotherapy-resistant cells on cancer progression, thereby improving patient outcomes.