Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity

Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blocking therapy has become a major pillar of cancer immunotherapy. Compared with antibodies targeting, small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed. Here we identified berberine (BBR), a proven anti-inflammation drug, as a negative regulator of PD-L1 from a set of traditional Chinese medicine (TCM) chemical monomers. BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells. In addition, BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumor-infiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). BBR triggered PD-L1 degradation through ubiquitin (Ub)/proteasome-dependent pathway. Remarkably, BBR selectively bound to the glutamic acid 76 of constitutive photomorphogenic-9 signalosome 5 (CSN5) and inhibited PD-1/PD-L1 axis through its deubiquitination activity, resulting in ubiquitination and degradation of PD-L1. Our data reveals a previously unrecognized antitumor mechanism of BBR, suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.

The roles of different signaling pathways and their related genes in the occurrence and development of colorectal cancer / 肿瘤研究与临床

Colorectal cancer is a kind of malignancies with high incidence in the worldwide, that is seriously harmed human health. So far the pathogenesis of the disease is not fully understood, this causing many difficulties to the diagnosis and treatment of the disease, and resulting in the cure rates of disease is not ideal. With the development of molecular genetics and molecular biology, many oncogenes and tumor suppressor genes have been found to be associated with the disease, and this made it is possible to reveal the pathogenesis of colorectal cancer at the molecular level. However, it is a complex and multi-step process from normal colorectal epithelial cells transformed to colorectal cancer cells, and it is the results of polygenic and multifactorial interactions. Now it is thought that the Wnt, TGF-beta, PI3K/Akt, MAPK and p53 signaling pathways are closely associated with pathogenesis of colorectal cancer. Based on the five kinds of signaling pathways as the main line, this article reviewed the roles of different signaling pathways and their related genes in the pathogenesis of colorectal cancer.