Cancer-associated fibroblasts (CAFs) are the main cancer-promoting component in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). α1,6-Fucosyltransferase (FUT8), the key enzyme catalyzing core α1,6-fucosylation (CF), plays a promoting role in multiple malignancies. In the current study, we investigated the function of FUT8 in CAFs and elucidated the mechanism through which FUT8 regulates the cancer-promoting capacity of CAFs in NSCLC. A bioinformatics analysis was performed to reveal the relationship between FUT8 and CAFs. Resected specimens from NSCLC patients were analyzed to assess the expression of FUT8 in CAFs. Primary CAFs and normal lung fibroblasts (NLFs) were extracted from NSCLC patient specimens and were co-cultured with NSCLC cell lines in a novel 3D-printed non-contact co-culture device. An In vivo CAF/NSCLC co-injection tumorigenesis assay was performed using nude mice to study the function of FUT8/CF in TME formation. The current study revealed that FUT8-mediated CF in CAFs plays a positive role in the cancer-promoting capacity of these cells. FUT8 overexpression was observed in CAFs isolated from some lung adenocarcinoma cases. Further investigation showed that FUT8/CF in CAFs promoted the formation of an invasive and malignant TME in vivo and in vitro, and the resulting NSCLC cells exhibited faster proliferation and increased invasiveness. EGFR signaling exerts a catalytic effect on the cancer-promoting capacity of CAFs and is regulated by the CF modification of the EGFR protein. AJCR Copyright © 2020.The development of chemo-resistance against 5-fluorouracil (5-FU) in tumor cells is one of the main debacles in colorectal cancer (CRC) patients. A recent combination of 5-FU with oxaliplatin or cetuximab drastically improves the survival rate in CRC patients; however, the toxicity issue cannot be evaded completely. Thus, searching for novel drug combinations with high specificity and low toxicity is seemingly important. Owing to the less undesirable effects of natural products on normal cells, here we investigated the synergistic antitumor effect of withaferin-A (WA) in combination with 5-FU. Our results demonstrate that the combination of WA and 5-FU induces a significant antiproliferative effect and modulates endoplasmic reticulum (ER) stress in favor of cell death in colorectal cancer (CRC) cells. Mechanistically, the combination upregulates the expression of ER stress sensors (BiP, PERK, CHOP, ATF-4, and eIF2α) and executes PERK axis mediated apoptosis in CRC cells. Additionally, the combined treatment of WA and 5-FU mediated ER stress induces autophagy and apoptosis, which were confirmed by immunoblotting, acridine orange (AO) staining and annexin-V FITC by flow cytometry. In contrast, inhibition of ER stress with salubrinal significantly decreases both autophagic and apoptotic cell populations. Moreover, pharmacological inhibition of either autophagy or apoptosis by their respective inhibitors 3-methyladenine (3-MA) or carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoro-methyl ketone (Z-VAD-FMK) decreases their respective population of cells but could not affect either of the population significantly. Finally, the combination attenuates the expression of β-catenin pathway associated proteins and arrests cell cycle at the G2M phase in CRC cells. In summary, the combination of WA and 5-FU decreases cell viability by inducing ER stress-mediated induction of autophagy and apoptosis, inhibiting the β-catenin pathway and arresting the cell cycle at a G2M phase in CRC cells. AJCR Copyright © 2020.Osteosarcoma is a common bone tumor, with a poor prognosis. New combinatorial therapies that sensitize anticancer drug-resistant osteosarcoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) are, therefore, required. The GTPase RhoA effector, Rho-associated coiled-coil forming protein kinase 2 (ROCK2), is well known for its roles in various types of cancer; however, its involvement osteosarcoma has not yet been scrutinized. In this study, we analyzed ROCK2 expression, clinicopathological features, and prognosis in osteosarcoma patients. Apoptosis, colony formation, and cell proliferation were analyzed using flow cytometry, colony formation assays, and CCK8 assays, respectively. Proteomics analysis was used to evaluate osteosarcoma progression. We found that adjacent tissues had lower ROCK2 expression levels than osteosarcoma tissues and the level of expression was related to osteosarcoma tumor size and prognosis. https://www.selleckchem.com/products/Cediranib.html Osteosarcoma prognosis was associated with ROCK2 expression level, which served as an independent marker in multivariate analysis. ROCK2 silencing inhibited proliferation in vivo and in vitro and triggered apoptotic osteosarcoma cell death. ROCK2 inhibited the TRAIL-mediated apoptotic pathway in osteosarcoma cells and promoted activation. Mechanistically, ROCK2 affected osteosarcoma progression and TRAIL resistance by modifying O-GlcNAcylation through O-GlcNAc transferase degradation. Taken together, our results demonstrated a unique mechanism whereby ROCK2 influences osteosarcoma progression and TRAIL resistance, hence improving osteosarcoma management. AJCR Copyright © 2020.Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors that arising from the adrenal medulla or extra-adrenal autonomic ganglia. Traditionally, PPGL was classified as benign or malignant based on the presence of distant metastasis at the time of initial surgery. However, according to WHO 2017 Classification of Tumors of Endocrine Organs, all PPGL has metastatic potential. The term "metastatic" is used, replacing "malignant" in this group of tumors. The prediction of PPGL's metastatic potential is a clinical concern, although many relevant indicators such as genetics, histology, pathology and molecular biology markers have been proved to be related to the metastasis of PPGL, but none of them is 100% predictive; various types of prediction systems had been created, but previous studies had demonstrated that they still need to be validated in multicenter studies. There is no unified clinical standard to differentiate metastatic from non-metastatic and a highly effective prediction system is of urgent need.