BackgroundNecroptotic susceptibility is probably an intrinsic weakness of cancer. Here, we report that resibufogenin, a member of bufadienolide family, suppresses the growth and metastasis of colorectal cancer (CRC) through induction of necroptosis in vivo.MethodsSW480 cells with stably expressing enhanced green fluorescence protein were xenografted to BALB/c-nu mice to observe the growth of tumors. Liver metastasis was observed by injection of MC38 cells beneath the splenic capsule of mice. Protein expression was determined by immunohistochemistry, immunofluorescence and western blot.ResultsConsolidated in vitro results indicate that resibufogenin has anti-proliferative activity on CRC cells. PI staining and transmission electron microscope imaging suggest that the cell death induced by resibufogenin are mainly through necrosis, which is further confirmed by the ineffectiveness of z-VAD, a pan-caspase general inhibitor. In particular, resibufogenin induced necrosis is substantially abrogated in receptor-interacting protein kinase 3 (RIPK3) knockout mouse embryo fibroblasts. The RIP3-dependent necrosis has been classified as necroptosis. Resibufogenin triggeres necroptosis through upregulating RIP3 and phosphorylating mixed lineage kinase domain-like protein at Ser358. Resibufogenin also activates the expression of PYGL, GLUD1 and GLUL in a RIP3-dependent manner. Resibufogenin exerts cytotoxic effect by inducing reactive oxygen species accumulation which can be neutralized by N-acetylcysteine. Remarkably, resibufogenin significantly suppresses liver-metastasis from spleen implantation. The anti-neoplastic effect of this compound can be abrogated by RIP3 knockdown.ConclusionResibufogenin suppresses growth and metastasis of CRC through RIP3-mediated necroptosis.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1580-x) contains supplementary material, which is available to authorized users.

Death receptors such as Fas are present in a variety of organs including liver and play an important role in homeostasis. What prevents these harmful receptors from forming homooligomers, clustering, and initiating the apoptotic pathway is not known. Here, we report the discovery of a cell survival mechanism by which Met, a growth factor receptor tyrosine kinase, directly binds to and sequesters the death receptor Fas in hepatocytes. This interaction prevents Fas self-aggregation and Fas ligand binding, thus inhibiting Fas activation and apoptosis. Our results describe a direct link between growth factor tyrosine kinase receptors and death receptors to establish a novel paradigm in growth regulation.

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Inducing angiogenesis is a hallmark of cancers that sustains tumor growth and metastasis. Neovascularization is a surprisingly early event during the multistage progression of cancer. Cinobufagin, an important bufadienolide originating from Chan Su, has been clinically used to treat cancer in China since the Tang dynasty. Here, we show that cinobufagin suppresses colorectal cancer ( CRC ) growth in vivo by downregulating angiogenesis. The hierarchized neovasculature is significantly decreased and the vascular network formation is disrupted in HUVEC by cinobufagin in a dose‐dependent way. Endothelial apoptosis is observed by inducing reactive oxygen species ( ROS ) accumulation and mitochondrial dysfunction which can be neutralized by N‐acetyl‐ l ‐cysteine ( NAC ). Expression of hypoxia‐inducible factor 1α ( HIF ‐1α) is reduced and phosphorylation of mTOR at Ser2481 and Akt at Ser473 is downregulated in HUVEC . Endothelial apoptosis is triggered by cinobufagin by stimulation of Bax and cascade activation of caspase 9 and caspase 3. Increased endothelial apoptosis rate and alterations in the HIF ‐1α/ mTOR pathway are recapitulated in tumor‐bearing mice in vivo. Further, the anti‐angiogenesis function of cinobufagin is consolidated based on its pro‐apoptotic effects on an EOMA ‐derived hemangioendothelioma model. In conclusion, cinobufagin suppresses tumor neovascularization by disrupting the endothelial mTOR / HIF ‐1α pathway to trigger ROS ‐mediated vascular endothelial cell apoptosis. Cinobufagin is a promising natural anti‐angiogenetic drug that has clinical translation potential and practical application value.

Cutaneous squamous cell carcinoma (cSCC) is the second common malignant cancer around the worldwide and is etiologically linked to ultraviolet radiation. miRNAs play an important role in the initiation and progression of cancers. However, the functions of miRNAs in cSCC remain to be elucidated. Here, we screened and identified miR-27a as a consistently downregulated miRNA after UVB irradiation in HaCaT cells. It was found that miR-27a expression was significantly decreased in cSCC cells and tissues. in vitro and in vivo experiments showed that miR-27a inhibited cell proliferation and invasion of cSCC cells. Mechanistically, EGFR was identified to be directly targeted by miR-27a and miR-27a suppressed the phosphorylation of EGFR and its downstream NF-κB signaling pathway. Overall, these findings suggest that downregulation of miR-27a promotes tumor growth and metastasis via targeting EGFR and its downstream NF-κB signaling pathway, reminding that miR-27a plays a vital role in the progression of cSCC and could be a new therapeutic target.

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Objective: To investigate the clinical effect of high intensity focused ultrasound (HIFU) ablation combined with gonadotropin-releasing hormone agonist (GnRH-a) and levonorgestrel-releasing intrauterine system (LNG-IUS) in the treatment of adenomyosis patients who failed to respond to drug therapies. Study design: A total of 47 patients with adenomyosis who had failed to respond to drug therapies and had no fertility desires were treated with HIFU combined with GnRH-a and LNG-IUS. The score of dysmenorrhea and menstrual volume were measured at pre and 6-, 12-, 18-, 24-month post-HIFU. Results: All patients completed HIFU ablation without major postoperative complications. Compared with the symptom scores before the HIFU treatment, the score of dysmenorrhea and menstrual volume decreased significantly at 6, 12, 18 and 24 months after HIFU treatment (p < 0.05), but no significant difference was observed between 6, 12, 18 and 24 months after HIFU (p > 0.05). The clinical success rate was 100%, 100%, 95.7% and 93.6% respectively at 6, 12, 18 and 24 months after the combined treatment. Conclusion:The combined therapeutic regimen of HIFU, GnRH-a and LNS-IUS is safe and effective, which can be an alternative treatment option for patients with adenomyosis who failed to respond to drug therapies to avoid adenomyomectomy or hysterectomy.

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