Malignant glioma is the most common and aggressive form of brain tumor with poor prognosis of survival. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent but is insufficient of inducing apoptosis in some types of gliomas. In this study, we showed that the small-molecule Mcl-1 inhibitor UMI-77 sensitized glioma cells to TRAIL treatment, as evidenced by cell viability assay, Annexin V staining and JC-1 staining. Combination of UMI-77 and TRAIL in glioma cells led to the activation of caspase-8 and Bid, cleavage of caspase-3 and poly-ADP ribose polymerase (PARP), accumulation of tBid in the mitochondria and release of cytochrome c into the cytosol. UMI-77 alone or in combination with TRAIL untethered pro-apoptotic Bcl-2 proteins Bim and Bak from the sequestration of Mcl-1 and promoted the conformational activation of Bak. Small hairpin RNA (shRNA) of Bid attenuated the cleavage of caspase-8, Bid, caspase-3 and PARP, and reduced the cytotoxicity of UMI-77 plus TRAIL as compared with control shRNA cells, indicating this synergy entails the crosstalk between extrinsic and intrinsic apoptotic signaling. Taken together, UMI-77 enhances TRAIL-induced apoptosis by unsequestering Bim and Bak, which provides a novel therapeutic strategy for the treatment of gliomas.

Classic fluorescent dyes, such as coumarin, naphthalimide, fluorescein, BODIPY, rhodamine, and cyanines, are cornerstones of various spectroscopic and microscopic methods, which hold a prominent position in biological studies. We recently found that 9-amino-benzo[c]cinnoliniums make up a novel group of fluorophores that can be used in biological studies. They are featured with a succinct conjugative push–pull backbone, a broad absorption band, and a large Stokes shift. They are potentially useful as a small-molecule alternative to R-phycoerythrin to pair with fluorescein in multiplexing applications.

The zinc finger transcription factor ZFX functions as an important regulator of self-renewal in multiple stem cell types, as well as a sex determinant of mammals. Moreover, ZFX expression is abnormally elevated in several cancers, and correlates with malignancy grade. To investigate its role in the pathogenesis of gliomas, we used lentivirus-mediated RNA interference (RNAi) to knockdown ZFX expression in human glioma cell lines. Our results demonstrate that ZFX plays a crucial role in glioma proliferation and survival, confirming recent reports. We also show for the first time that ZFX knockdown decreases the in vivo growth potential of U87 glioma xenografts in both subcutaneous and intracranial models in nude mice. We conclude that lentivirus-mediated RNAi targeting of ZFX may serve as a promising strategy for glioma therapy.

Neuronal morphogenesis plays an important role in neuronal development. TC10β/CDC42 GTPase-activating protein (TCGAP) is known to be a brain-enriched multiple domain protein, but its role in neuronal development process remains poorly understood. In the present study, we showed that TCGAP positively regulated dendritic outgrowth and spine formation in developing cortical neurons. Knocking down TCGAP by RNA interference led to a decrease in the overall length of dendrite arbors and the number of dendrite branches both in vitro and in vivo. Overexpressing TCGAP in cultured cortical neurons increased dendritic outgrowth and branching. Moreover, overexpressing TCGAP lead to an increase of spine density while knocking-down TCGAP decreased spine density in vivo. The defect by downregulating TCGAP could be rescued by expressing a knock-down resistant form of TCGAP both in vivo and in vitro. In contrast, neither downregulating nor overexpressing TCGAP had any effect on axonal morphogenesis in primary cortical neuron cultures. Together, our findings suggest that TCGAP regulates neuronal morphogenesis in developing cortical neurons at both early and late stage.Highlights▶Overexpression of TCGAP led to increases of dendritic outgrowth in vitro. ▶Knocking down TCGAP led to decreases of dendritic outgrowth both in vitro and in vivo. ▶TCGAP positively regulates spine formation in vivo in a late stage of neuron development. ▶TCGAP is not essential for axonal morphogenesis.