Fig. 3.

(A) Signaling of TGF-β in PCa. The TGF-β1 activates the TGF-β signaling after binding with the TGF-beta receptor 2 (TGF-βR2), which leads to the stimulation of EMT in PCa. miR-20b-5p, TGF-βR2, and E2F1 are known to promote the TGF-β1 prompted EMT of PCa cells, (B) Signaling of TNF-α with TGF-β and interleukins in PCa. (i) High levels of TNF-α, together with the IL-β, and IL-6 in the presence of extracellular histones, causes enhanced migration rate of PCa cells, (ii) MiR-130b, inhibit the expression of TNF-α via diminishing NF-κB axis and its downstream target gene vascular endothelial growth factor-A (VEGFA), (iii) Nω-nitro-l-arginine methyl ester (L-NAME), increases the expression of TNF-α, which is leveraged by plant enzyme validux (PEV) to suppress the progression of PCa.

Abbreviations- PCa- prostate cancer, ADT-PCa-ADT androgen deprivation therapy receiving prostate cancer, IL- interleukin, TNF-α- tumor necrosis factor α, TGF-β- transforming growth factor β, NGR-TNF- tumor necrosis factor-α (TNF-α) to the tumor endothelium with Cys–Asn–Gly–Arg–Cys–Gly–TNF, NFKB- nuclear factor kappa-light-chain-enhancer of activated B cells, PDL-1-programmed death-ligand 1, CTLs- cytotoxic T lymphocytes, ICB- immune checkpoint blockade, PD-1- Programmed cell death protein 1, CTT-4- cytotoxic T-lymphocyte-associated protein 4, VEGFA- vascular endothelial growth factor-A, PAGE4- prostate-associated gene 4, l-NAME-Nω-nitro-l-arginine methyl ester, PEV- plant enzyme validux, CAFs-cancer-associated fibroblast, TGF-βR2- transforming growth factor-beta receptor 2, EMT-epithelial-mesenchymal transition, IFITM3-interferon-inducible transmembrane protein 3, MAPK- mitogen-activated protein kinase, E2F1-E2F Transcription Factor 1.