Never in Mitosis (NIMA) Related Kinase 2 (NEK2) plays a key role in regulating mitotic processes, including centrosome duplication and separation, microtubule stabilization, kinetochore attachment and spindle assembly checkpoint. NEK2 is aberrantly overexpressed in a wide variety of human cancers and has been implicated in various aspects of malignant transformation, including tumorigenesis, drug resistance and tumor progression. The close relationship between NEK2 and cancer has made it an attractive target for anticancer therapeutic development; however, the mechanisms of how NEK2 coordinates altered signaling to malignant transformation remains unclear. In this paper, we discuss the functional roles of NEK2 in cancer development; highlight some of the significant NEK2 signaling in cancer, and summarize recent advances in the development of NEK2 inhibitors.

Cancer cachexia is a kind of whole-body metabolic disorder syndrome accompanied by severe wasting of muscle tissue in which cancer exosomes may be involved. Analysis of clinical samples showed that the serum exosome concentrations were correlated with the development of cancer cachexia. Exosomes secreted by C26 cells could decrease the diameter of C2C12 myotubes in vitro and decrease mouse muscle strength and tibialis anterior (TA) muscle weight in vivo. GW4869, an inhibitor of exosome excretion, ameliorated muscle wasting in C26 tumor-bearing mice. MicroRNA (miRNA) sequencing (miRNA-seq) analysis suggested that miR-195a-5p and miR-125b-1-3p were richer in C26 exosomes than in exosomes secreted from MC38 cells (non-cachexic). Both miR-195a-5p and miR-125b-1-3p mimics could induce atrophy of C2C12 myoblasts. Downregulation of Bcl-2 and activation of the apoptotic signaling pathway were observed in C2C12 myoblasts transfected with miR-195a-5p and miR-125b-1-3p mimics, in the gastrocnemius muscle of C26 tumor-bearing mice and in the TA muscle injected with C26 exosomes. Results of dual-luciferase assay confirmed the targeting of miR-195a-5p/miR-125b-1-3p to Bcl-2. Overexpression of Bcl-2 successfully reversed atrophy of C2C12 myoblasts induced by the two miRNA mimics. These results suggested that cancer exosome enriched miRNAs might induce muscle atrophy by targeting Bcl-2-mediated apoptosis.

Background: Cancer cachexia is a multifactorial metabolic syndrome in which bile acid (BA) metabolism might be involved. The aim of the present study was to clarify the contribution of liver and gut microbiota to BA metabolism disturbance in cancer cachexia and to check the possibility of targeting BA metabolism using agents such as tauroursodeoxycholic acid (TUDCA) for cancer cachexia therapy.Methods: The BA profiles in liver, intestine, and serum of mice with cancer cachexia induced by inoculation of colon C26 tumour cells were analysed using metabolomics methods and compared with that of control mice. Proteomic analysis of liver protein expression profile and 16S rRNA gene sequencing analysis of gut microbiota composition in cancer cachexia mice were conducted. Expression levels of genes related to farnesoid X receptor (FXR) signalling pathway in the intestine and liver tissues were analysed using RT–PCR analysis. The BA profiles in serum of clinical colon cancer patients with or without cachexia were also analysed and compared with that of healthy volunteers. The effects of TUDCA in treating cancer cachexia mice were observed.Results: In the liver of cancer cachexia mice, expression of BA synthesis enzymes was inhibited while the amount of total BAs increased (P < 0.05). The ratios of conjugated BAs/un‐conjugated BAs significantly increased in cancer cachexia mice liver (P < 0.01). Gut microbiota dysbiosis such as decrease in Lachnospiraceae and increase in Enterobacteriaceae was observed in the intestine of cancer cachexia mice, and microbial metabolism of BAs was reduced. Increase in expression of FGF15 in intestine (P < 0.01) suggested the activation of FXR signalling pathway which might contribute to the regulation of BA synthesis enzymes, transporters, and metabolic enzymes. Increase in the BA conjugation was observed in the serum of cancer cachexia mice. Results of clinical patients showed changes in BA metabolism, especially the increase in BA conjugation, and also suggested compensatory mechanism in BA metabolism regulation. Oral administration of 50 mg/kg TUDCA could significantly ameliorate the decrease in body weight (P < 0.001), muscle loss (P < 0.001), and atrophy of heart and liver (P < 0.05) in cancer cachexia mice without influence on tumour growth.Conclusions: Bile acid metabolism dysregulation such as decrease in BA synthesis, increase in BA conjugation, and decrease in BA microbial metabolism was involved in development of cancer cachexia in mice. Targeting BA metabolism using agents such as TUDCA might be helpful for cancer cachexia therapy.

Background: Atractylenolide I (AI) is a natural sesquiterpene lactone isolated from Atractylodes macrocephala Koidz, known as Baizhu in traditional Chinese medicine. AI has been found to ameliorate cancer cachexia in clinic cancer patients and in tumour‐bearing mice. Here, we checked the influence of AI on biogenesis of IL‐6 and extracellular vesicles (EVs) in cancer cachexia mice and then focused on studying mechanisms of AI in inhibiting the production of tumour‐derived EVs, which contribute to the ameliorating effects of AI on cancer cachexia.Methods: C26 tumour‐bearing BALB/c mice were applied as animal model to examine the effects of AI (25 mg/kg) in attenuating cachexia symptoms, serum IL‐6 and EVs levels. IL‐6 and EVs secretion of C26 tumour cells treated with AI (0.31–5 μM) was further observed in vitro. The in vitro cultured C2C12 myotubes and 3T3‐L1 mature adipocytes were used to check the potency of conditioned medium of C26 cells treated with AI (0.625–5 μM) in inducing muscle atrophy and lipolysis. The glycolysis potency of C26 cells under AI (0.31–5 μM) treatment was evaluated by measuring the extracellular acidification rate using Seahorse XFe96 Analyser. Levels of related signal proteins in both in vitro and in vivo experiments were examined using western blotting to study the possible mechanisms. STAT3 overexpression or knockout C26 cells were also used to confirm the effects of AI (5 μM).Results: AI ameliorated cancer cachexia symptoms (P < 0.05), improved grip strength (P < 0.05) and decreased serum EVs (P < 0.05) and IL‐6 (P < 0.05) levels of C26 tumour‐bearing mice. AI directly inhibited EVs biogenesis (P < 0.001) and IL‐6 secretion (P < 0.01) of cultured C26 cells. The potency of C26 medium in inducing C2C12 myotube atrophy (+59.54%, P < 0.001) and 3T3‐L1 adipocyte lipolysis (+20.73%, P < 0.05) was significantly attenuated when C26 cells were treated with AI. AI treatment inhibited aerobic glycolysis and the pathway of STAT3/PKM2/SNAP23 in C26 cells. Furthermore, overexpression of STAT3 partly antagonized the effects of AI in suppressing STAT3/PKM2/SNAP23 pathway, EVs secretion, glycolysis and the potency of C26 medium in inducing muscle atrophy and lipolysis, whereas knockout of STAT3 enhanced the inhibitory effect of AI on these values. The inhibition of AI on STAT3/PKM2/SNAP23 pathway was also observed in C26 tumour tissues.Conclusions: AI ameliorates cancer cachexia by decreasing the production of IL‐6 and EVs of tumour cells. The decreasing effects of AI on EVs biogenesis are based on its inhibition on STAT3/PKM2/SNAP23 pathway.

Tumor-derived exosomes are emerging mediators of cancer cachexia, a kind of multifactorial syndrome characterized by serious loss of skeletal muscle mass and function. Our previous study had showed that microRNAs in exosomes of C26 colon tumor cells were involved in induction of muscle atrophy. Here, we focus on studying proteins in tumor-derived exosomes which might also contribute to the development of cancer cachexia. Results of comparing the protein profiles of cachexic C26 exosomes and non-cachexic MC38 exosomes suggested that growth differentiation factor 15 (GDF-15) was rich in C26 exosomes. Western blotting analysis confirmed the higher levels of GDF-15 in C26 cells and C26 exosomes, compared with that of MC38 cells. Results of animal study also showed that GDF-15 was rich in tumor tissues, serum exosomes, and gastrocnemius (GA) muscle tissues of C26 tumor-bearing mice. GDF-15 protein could directly induce muscle atrophy of cultured C2C12 myotubes via regulating Bcl-2/caspase-3 pathways. What’s more, overexpression of GDF-15 in MC38 cells could increase the potency of MC38 conditioned medium or exosomes in inducing muscle atrophy. Knockdown of GDF-15 in C26 cells decreased the potency of C26 conditioned medium or exosomes in inducing muscle atrophy. These results suggested that GDF-15 in tumor-derived exosomes could contribute to induction of muscle atrophy and also supported the possibility of targeting GDF-15 in treatment of cancer cachexia.