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[International Journal of Molecular Sciences]Anti-Cancer Roles of Probiotic-Derived P8 Protein in Colorectal Cancer Cell Line DLD-1


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Anti-Cancer Roles of Probiotic-Derived P8 Protein in Colorectal Cancer Cell Line DLD-1

R&D Center, Cell Biotech, Co., Ltd., 50 Aegibong-ro 409 Beon-gil, Gaegok-ri, Wolgot-myeon, Gimpo-si 10003, Gyeonggi-do, Republic of Korea

Figure 7. P8 has anti-proliferative activity in Wnt signaling. (A) Mechanism with which P8 enters DLD-1 cells and directly down-regulates the GSK3β gene. P8, which enters the cytosol through endocytosis, binds to KPNA3, a component of the importin transport system, at the nuclear envelope. The P8-KPNA3 complex is translocated into the nucleus through NPC. Following its release from the importin transport system, P8 binds to a specific intron sequence on the GSK3β gene, significantly inhibiting GSK3β gene transcription. (B) Wnt signaling in CRC is a major modulator of cell proliferation, self-renewal, differentiation, and tissue homeostasis during tumor development. Hyper-activation of Wnt signaling is observed in almost CRCs. When Wnt signaling is suppressed, GSK3β initiates a phosphorylation cascade, phosphorylating β-catenin and resulting in its subsequent degradation. By contrast, activation of Wnt signaling results in GSK3β inactivation by phosphorylation (S9), resulting in non-phosphorylation of β-catenin, with the latter remaining active and promoting cell proliferation. Binding of P8 to GSK3β inhibits the phosphorylation (S9) of GSK3β by the protein kinases AKT, CK1ε, and PKA. Active GSK3β, in turn, phosphorylates β-catenin, resulting in its degradation. Consequently, P8 can induce cell cycle arrest in CRC cells, even when Wnt signaling is activated.