Impairment of Hyaluronan-Related Glycocalyx Inhibits Macropinocytosis in Cancer Cells via p21 Upregulation

Macropinocytosis (MP) in cancer cells is an endocytic process for nutrient extraction initiated by membrane ruffling that supports tumor progression. Hyaluronan (HA), a major component of glycocalyx coating the surface of living cells, is reported to influence the membrane morphology. However, whether HA-related glycocalyx (HA-GCX) regulates MP through membrane reconstruction remains unclear. Here, we demonstrated that the HA-GCX thickness was positively correlated with MP activity in cancer cells. Intriguingly, the disruption of HA-GCX could suppress MP by decreasing membrane ruffle formation. Furthermore, the knockdown of cyclin-dependent kinase inhibitor 1 (CDKN1A/p21) and its downstream matrix metalloproteinase (MMP) 1/9, which were identified to be significantly upregulated following HA-GCX removal, could rescue MP. Importantly, the breakdown of HA-GCX could impede cancer cell proliferation through inhibition of MP. Taken together, our study revealed a novel regulatory role of HA-GCX in MP, which might provide a promising therapeutic avenue in cancer treatment.