Polysaccharopeptide from Coriolus versicolor suppresses quiescent cancer cell reactivation through cyclin D3–CDK4/6 degradation and NF-κB suppression

Cancer recurrence remains a major challenge in prostate cancer (PCa), in part because quiescent cancer cells (QCCs) can survive conventional therapies and subsequently re-enter the cell cycle. Bioactive polysaccharides from food and medicinal mushrooms are increasingly investigated as nutraceutical ingredients for disease prevention and adjunctive health management. Polysaccharopeptide (PSP), a protein-bound polysaccharide derived from the mycelia of Coriolus versicolor, has a long history of oral use as an adjunctive bioactive preparation. Here, PSP inhibited QCC reactivation in LNCaP and PC-3 cells and restrained recurrent tumor growth in a quiescent PC-3 xenograft model. Mechanistically, PSP shortened the protein half-lives of Cyclin D3, CDK4, and CDK6, while proteasome inhibition attenuated their loss, supporting proteasome-dependent destabilization of the Cyclin D3–CDK4/6 axis. PSP also suppressed canonical and noncanonical NF-κB signaling, reduced nuclear accumulation of p65 and p52, and decreased NF-κB transcriptional activity, accompanied by decreased TNF-α and increased IL-10 expression. Oral PSP administration delayed recurrent tumor growth and prolonged overall survival in the xenograft model. Collectively, these findings identify QCC reactivation as a previously unrecognized cellular process responsive to PSP and provide mechanistic and preclinical support for further evaluation of this mushroom-derived bioactive preparation as an adjunctive strategy for recurrence-oriented PCa management.