E3 ligase MG53 suppresses tumor growth by degrading cyclin D1

Due to the essential role of cyclin D1 in regulating transition from G1 to S phase in cell cycle,aberrant cyclin D1 expression is a major oncogenic event in many types of cancers.In particular,the dysregulation of ubiquitination-dependent degradation of cyclin D1 contributes to not only the pathogenesis of malignancies but also the refractory to cancer treatment regiments with CDK4/6 inhibitors.Here we show that in colorectal and gastric cancer patients,MG53 is downregulated in more than 80%of tumors compared to the normal gastrointestinal tissues from the same patient,and the reduced MG53 expression is correlated with increased cyclin D1 abundance and inferior survival.Mechanistically,MG53 catalyzes the K48-linked ubiquitination and subsequent degradation of cyclin D1.Thus,increased expression of MG53 leads to cell cycle arrest at G1,and thereby markedly suppresses cancer cell proliferation in vitro as well as tumor growth in mice with xenograft tumors or AOM/DSS induced-colorectal cancer.Consistently,MG53 deficiency results in accumulation of cyclin D1 protein and accelerates cancer cell growth both in culture and in animal models.These findings define MG53 as a tumor suppressor via facilitating cyclin D1 degradation,highlighting the therapeutic potential of targeting MG53 in treating cancers with dysregulated cyclin D1 turnover.

Theranostic nanosystem mediating cascade catalytic reactions for effective immunotherapy of highly immunosuppressive and poorly penetrable pancreatic tumor

The dense desmoplastic stroma and immunosuppressive microenvironment of pancreatic cancer hinder the penetration of drugs and induce a considerable resistance to conventional chemoradiotherapy. Although nanomedicine has recently shown attractive potential in cancer immunotherapy, it remains a great challenge to achieve efficient drug delivery and potent immune activation.Here, a stimuli-responsive nanosystem, comprising superparamagnetic iron oxide nanocrystals and nitric oxide(NO) donors,was developed for in-situ triggered catalytic cascade reaction to produce abundant free radicals and remodel the anti-tumor immunity. The nanosystem was activated in the tumor microenvironment to produce NO which dilated the tumor vasculature for efficient drug delivery, and the iron oxide nanocrystals catalyzed the reaction of NO to generate reactive oxygen-nitrogen species(RONS) with high cytotoxicity. Moreover, owing to the catalytic cascade reactions mediated by the nanosystem, the tumor associated macrophages(TAMs) were converted to a proinflammatory M1 phenotype and tumor infiltration of effector T cells was promoted to result in potent anti-tumor immunotherapy which could be readily monitored with magnetic resonance imaging(MRI).