Cdc42 Regulates the Expression of Cytoskeleton and Microtubule Network Proteins to Promote Invasion and Metastasis of Progeny Cells Derived from CoCl₂-induced Polyploid Giant Cancer Cells

Abstract

Purpose: Our previous studies have shown that CoCl 2 can induce the formation of polyploid giant cancer cells (PGCCs) and PGCCs could produce progeny cells via asymmetric division. In this study, the molecular mechanism by which PGCCs generate progeny cells with high invasion and migration abilities was explored. Methods: In this study, PGCCs induced by CoCl 2 produced progeny cells via asymmetric division, which was observed dynamically using laser scanning confocal microscopy. Cell cycle in LoVo and Hct116 before and after CoCl 2 treatment was analyzed by flow cytometry. Cell function experiments, co-immunoprecipitation, mass spectrometry analysis, ML141 treatment, western blotting, and siRNA transfection experiments were used to demonstrate that Cdc42/PAK1 was involved in the regulation of cytoskeleton expression. The proliferation, migration, and invasion abilities of PGCCs and progeny cells were compared in PGCCs and progeny cells with and without inhibiting the expression of Cdc42 and PAK1. Results: G2/M phase arrest appeared in CoCl 2- treated LoVo and Hct116 cells. After CoCl 2 treatment, an increased expression of Cdc42 and PAK1 led to a decrease in the expression of stathmin and an increase in the expression of phosphorylated stathmin, which is located in the nucleus of PGCCs and progeny cells. PTPN14 negatively regulates the expression of PAK1 and p38MAPK. Low levels of PTPN14 expression, a downstream regulatory protein of stathmin, endows progeny tumor cells generated by PGCCs with the ability to invade and metastasize. The expression of PKA1α, cathepsin B, and D increased in CoCl 2 -treated cells compared with that in the control cells, associated with the infiltration and migration of PGCCs with their progeny cells. Conclusion: CoCl 2 -induced overexpression of Cdc42 plays a critical role in increasing the infiltration and migration abilities of PGCCs and progeny cells by regulating cytoskeleton protein expression.

Polyploid giant cancer cells induced by Docetaxel exhibit a senescence phenotype with the expression of stem cell markers in ovarian cancer cells

“…Although most of PGCCs succumb to cell death, some can survive and acquire cancer stem cells properties [ 19 , 23 ]. PGCCs are also considered to be a key factor in the process of tumorigenesis, metastasis and therapy resistance [ 24 , 25 ]. It seems necessary to pay more attention to PGCCs, a cancer cell subpopulation, in different aspects of tumor biology and therapy.…”

Dormant cancer cells and polyploid giant cancer cells: The roots of cancer recurrence and metastasis

“…121 Several studies have reported cell cycle arrest in PGCCs. [122][123][124][125][126] In current reports, terminologies related to cell cycle arrest of PGCCs include G2 cell cycle arrest, G Alert /spG0/G0 cells, arrested in the G0/G1 phase, quiescence, slow-cycling states, dormant state and proliferative arrest. Alhaddad L et al discussed the radioresistance related to the proportion of dormant PGCCs by the Ki-67/EdU staining features enriching in three subpopulations (G Alert , spG0, G0).…”

“…Cdc42 overexpression takes a part in the invasion and migration of PGCCs and daughter cells. 123 In summary, PGCCs maintain cell cycle arrest and exhibit high migration and invasion rates when dormant.…”

“…The highly invasive and migratory characteristics of PGCCs-derived daughter cells have been demonstrated in many studies. 24,123,134,149,[163][164][165][166] PGCCs-derived daughter cells can easily metastasize to the lymph nodes or distant organs by expressing EMT-related proteins (Snail, Slug and Twist). 167 Ezrin, S100A4 and 14-3-3ζ/δ are involved in the migration and invasion of PGCCs-derived daughter cells via cytoskeletal constructions.…”

Polyploid giant cancer cells: origin, possible pathways of formation, characteristics, and mechanisms of regulation

“…A recent study by Zheng et al found that after CoCl 2 treatment, the expression of Cdc42 and PAK1 increased, promoting the nuclear expression of phosphorylated stathmin (STMN1). This process enhances the proliferation, invasion, and migration of PGCCs and their daughter cells through cytoskeletal remodeling ( Zheng et al, 2023 ). Targeting PGCCs and their progeny can thus be a strategic direction.…”