Demethylzeylasteral is one of the extracts of Tripterygium wilfordii Hook F, which plays important roles in multiple biological processes such as inflammation inhibition, as well as immunosuppression. However, anti-cancer function and the underlying mechanisms of demethylzeylasteral in melanoma cells remain unclear. In this study, we demonstrate that demethylzeylasteral has an anti-tumor property in melanoma cells. Demethylzeylasteral not only inhibits cell proliferation through cell cycle arrest at S phase, but also induces cell apoptosis in melanoma cells. MCL1 is an anti-apoptotic protein in BCL2 family, and amplifies frequently in multiple human cancers. MCL1 is also known as a potential contributor for the resistance of BCL2 inhibitors, as well as various chemotherapeutic drugs. MCL1 is, therefore, regarded as a potential target for cancer therapy. Here, for the first time, we unveil that demethylzeylasteral suppresses the expression of MCL1. Interestingly, MCL1 interacts with S phase-related protein CDK2, and thereby inhibits it’s ubiquitin-dependent degradation. Together, demethylzeylasteral is a promising anti-tumor compound in melanoma cells. Demethylzeylasteral is also a potential inhibitor of MCL1.

Treatment of pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge. There is an urgent need to develop novel strategies to enhance survival and improve patient prognosis. MicroRNAs (miRNAs) play critical roles as oncogenes or tumor suppressors in the regulation of cancer development and progression. In this study, we demonstrate that low expression of miR-15a is associated with poor prognosis of PDAC patients. miR-15a expression is reduced in PDAC while closely related miR-16 expression remains relatively unchanged. miR-15a suppresses several important targets such as Wee1, Chk1, Yap-1, and BMI-1, causing cell cycle arrest and inhibiting cell proliferation. Ectopic expression of miR-15a sensitizes PDAC cells to gemcitabine reducing the half maximal inhibitory concentration (IC50) more than 6.5-fold. To investigate the therapeutic potential of miR-15a, we used a modified miR-15a (5-FU-miR-15a) with uracil (U) residues in the guide strand replaced with 5-fluorouracil (5-FU). We demonstrated enhanced inhibition of PDAC cell proliferation by 5-FU-miR-15a compared to native miR-15a. In vivo we showed the therapeutic power of 5-FU-miR-15a alone or in combination with gemcitabine with near complete elimination of PDAC lung metastatic tumor growth. These results support the future development of 5-FU-miR-15a as a novel therapeutic agent as well as a prognostic biomarker in the clinical management of PDAC.

(2015) FGFR3/fibroblast growth factor receptor 3 inhibits autophagy through decreasing the ATG12-ATG5 conjugate, leading to the delay of cartilage development in achondroplasia, Autophagy, 11:11, 1998, DOI: 10.1080/15548627.2015 G369C/C , constitutively active Fgfr3 mice; ATG5, autophagy-related 5; ATG12, autophagy-related 12; coIP, coimmunoprecipitation; CTGF/CCN2, connective tissue growth factor; FGFR3, fibroblast growth factor receptor 3; FGF, fibroblast growth factor; K D , kinase domain; PBS, phosphate-buffered saline; R3CKO, fgfr3 flox/flox mice, Fgfr3 conditional knockout mice; R3KO mice, fgfr3 global knockout mice; RCS, rat chondrosarcoma; Sumf1, sulfatase modifying factor 1; TM, 4-hydroxy tamoxifen; WT, wild type; YFP-PCA, yellow fluorescent protein-based protein-fragment complementation assay.FGFR3 (fibroblast growth factor receptor 3) is a negative regulator of endochondral ossification. Gain-of-function mutations in FGFR3 are responsible for achondroplasia, the most common genetic form of dwarfism in humans. Autophagy, an evolutionarily conserved catabolic process, maintains chondrocyte viability in the growth plate under stress conditions, such as hypoxia and nutritional deficiencies. However, the role of autophagy and its underlying molecular mechanisms in achondroplasia remain elusive. In this study, we found activated FGFR3 signaling inhibited autophagic activity in chondrocytes, both in vivo and in vitro. By employing an embryonic bone culture system, we demonstrated that treatment with autophagy inhibitor 3-MA or chloroquine led to cartilage growth retardation, which mimics the effect of activated-FGFR3 signaling on chondrogenesis. Furthermore, we found that FGFR3 interacted with ATG12-ATG5 conjugate by binding to ATG5. More intriguingly, FGFR3 signaling was found to decrease the protein level of ATG12-ATG5 conjugate. Consistently, using in vitro chondrogenic differentiation assay system, we showed that the ATG12-ATG5 conjugate was essential for the viability and differentiation of chondrocytes. Transient transfection of ATG5 partially rescued FGFR3-mediated inhibition on chondrocyte viability and differentiation. Our findings reveal that FGFR3 inhibits the autophagic activity by decreasing the ATG12-ATG5 conjugate level, which may play an essential role in the pathogenesis of achondroplasia.

Collectively, our findings demonstrate that OIP5 promotes glioblastoma progression and metastasis, suggesting that OIP5 is a potential target for anticancer therapy.

Numerous long noncoding RNAs (lncRNAs) are aberrantly expressed in pancreatic cancer (PC); however, their functions and mechanisms in cancer progression are largely unknown. In this study, we identified a novel PC-associated lncRNA, RUNX1-IT1, that was significantly upregulated in PC patient samples from multiple centers and associated with poor prognosis. In vitro and in vivo, alterations in RUNX1-IT1 expression markedly affected PC proliferation, migration and invasion. RUNX1-IT1 contributed to the progression of PC by interacting with the adjacent gene RUNX1. Rescue experiments showed that RUNX1 reduced the cancer-promoting effect of RUNX1-IT1. RNA-seq analysis after silencing RUNX1-IT1 and RUNX1 highlighted alterations in the common target C-FOS. Mechanistically, we demonstrated that RUNX1-IT1 was a trans-acting factor that participated in the proliferation, migration and invasion of PC by recruiting RUNX1 to the C-FOS gene promoter. Furthermore, RUNX1-IT1 enhanced the transcription of the RUNX1 gene, indicating its potential as a cis-regulatory RNA involved in the upstream regulation of RUNX1. Overall, RUNX1-IT1 is a crucial oncogenic lncRNA that activates C-FOS expression by regulating and recruiting RUNX1 and is a potential prognostic biomarker and therapeutic target for PC.