Exosomes are well-known key mediators of intercellular communication and contribute to various physiological and pathological processes. Their biogenesis involves four key steps, including cargo sorting, MVB formation and maturation, transport of MVBs, and MVB fusion with the plasma membrane. Each process is modulated through the competition or coordination of multiple mechanisms, whereby diverse repertoires of molecular cargos are sorted into distinct subpopulations of exosomes, resulting in the high heterogeneity of exosomes. Intriguingly, cancer cells exploit various strategies, such as aberrant gene expression, posttranslational modifications, and altered signaling pathways, to regulate the biogenesis, composition, and eventually functions of exosomes to promote cancer progression. Therefore, exosome biogenesis-targeted therapy is being actively explored. In this review, we systematically summarize recent progress in understanding the machinery of exosome biogenesis and how it is regulated in the context of cancer. In particular, we highlight pharmacological targeting of exosome biogenesis as a promising cancer therapeutic strategy.

SUN2, a key component of LINC (linker of nucleoskeleton and cytoskeleton) complex located at the inner nuclear membrane, plays unknown role in lung cancer. We found that SUN2 expression was decreased in lung cancer tissue compared with paired normal tissues and that higher SUN2 levels predicted better overall survival and first progression survival. Overexpression of SUN2 inhibits cell proliferation, colony formation and migration in lung cancer, whereas knockdown of SUN2 promotes cell proliferation and migration. Additionally, SUN2 increases the sensitivity of lung cancer to cisplatin by inducing cell apoptosis. Mechanistically, we showed that SUN2 exerts its tumor suppressor functions by decreasing the expression of GLUT1 and LDHA to inhibit the Warburg effect. Finally, our results provided evidence that SIRT5 acts, at least partly, as a negative regulator of SUN2.Taken together, our findings indicate that SUN2 is a key component in lung cancer progression by inhibiting the Warburg effect and that the novel SIRT5/SUN2 axis may prove to be useful for the development of new strategies for treating the patients with lung cancer.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies resistant to current chemotherapies or radiotherapies, which makes it urgent to identify new therapeutic targets for HCC. In this study, we found that checkpoint kinase 1 (CHK1) was frequently overexpressed and correlated with poor clinical outcome in patients with HCC. We further showed that the CHK1 inhibitor GÖ6976 was capable of sensitizing HCC cells to cisplatin, indicating that CHK1 may have oncogenic function in HCC. We found that CHK1 phosphorylated the tumor suppressor spleen tyrosine kinase (L) (SYK[L]) and identified the phosphorylation site at Ser295. Furthermore, CHK1 phosphorylation of SYK(L) promoted its subsequent proteasomal degradation. Expression of a nonphosphorylated mutant of SYK(L) was more efficient at suppressing proliferation, colony formation, mobility, and tumor growth in HCC lines. Importantly, a strong inverse correlation between the expression levels of CHK1 and SYK(L) was observed in patients with HCC. Collectively, our data demonstrate that SYK(L) is a substrate of CHK1 in tumor cells and suggest that targeting the CHK1/SYK(L) pathway may be a promising strategy for treating HCC.

Purpose: Aspirin has recently been reported to reduce both the incidence and the risk of metastasis in colon cancer. However, there is no evidence at the cellular levels or in the animal models for such an effect of aspirin on cancer metastasis.Experimental Design: MTT assay, colony formation assay, and apoptosis assay were employed to analyze the effects of aspirin on the osteosarcoma cell viability in vitro. The NF-kB activity was measured by the NF-kB p65 luciferase reporter. Western blotting was used to analyze the proteins in cells. The migration and invasion abilities of osteosarcoma cells in vitro were measured by the Transwell assay. Xenograft-bearing mice were used to assess the roles of aspirin in both tumor growth and metastasis of osteosarcoma in vivo (n ¼ 5-8 mice/group). An unpaired Student t test or ANOVA with the Bonferroni post hoc test were used for the statistical comparisons.Results: Aspirin reduced cell viability in a dose-and timedependent manner in osteosarcoma cell lines, and aspirin synergistically sensitized osteosarcoma cells to cisplatin (DDP) in vitro and in vivo (P < 0.001). Moreover, aspirin markedly repressed the migration and invasion of osteosarcoma cells in vitro (P < 0.001), and dramatically diminished the occurrence of osteosarcoma xenograft metastases to the lungs in vivo (P < 0.001). Mechanistically, aspirin diminishes osteosarcoma migration, invasion, and metastasis through the NF-kB pathway.Conclusions: Aspirin suppresses both the growth and metastasis of osteosarcoma through the NF-kB pathway at the cellular level and in the animal models.