BMP8A promotes survival and drug resistance via Nrf2/TRIM24 signaling pathway in clear cell renal cell carcinoma.

There is increasing evidence that bone morphogenetic proteins (BMP) are involved in the proliferation and drug tolerance of kidney cancer. However, the molecular mechanism of BMP8A in renal cell proliferation and drug tolerance is not clear. Here we showed that BMP8A was highly expressed in renal cell carcinoma, which suggests a poor prognosis of ccRCC. Promotion of cell proliferation and inhibition of apoptosis were detected by CCK-8 assay, Trypan Blue staining, flow cytometry and bioluminescence. BMP8A promoted resistance of As2 O3 by regulating Nrf2 and Wnt pathways in vitro and in vivo. Mechanistically, BMP8A enhanced phosphorylation of Nrf2, which, in turn, inhibited Keap1-mediated Nrf2 ubiquitination and, ultimately, promoted nuclear translocation and transcriptional activity of Nrf2. Nrf2 regulates the transcription of TRIM24 detected by ChIP-qPCR. BMP8A was highly expressed in ccRCC, which suggests a poor prognosis. BMP8A was expected to be an independent prognostic molecule for ccRCC. On the one hand, activated Nrf2 regulated reactive oxygen balance, and on the other hand, by regulating the transcription level of TRIM24, it was involved in the regulation of the Wnt pathway to promote the proliferation, invasion and metastasis of ccRCC and the resistance of As2 O3 . Taken together, our findings describe a regulatory axis where BMP8A promotes Nrf2 phosphorylation and activates TRIM24 to promote survival and drug resistance in ccRCC.

Blockage of potassium channel inhibits proliferation of glioma cells via increasing reactive oxygen species.

The potassium (K(+)) channel plays an important role in the cell cycle and proliferation of tumor cells, while its role in brain glioma cells and the signaling pathways remains unclear. We used tetraethylammonium (TEA), a nonselective antagonist of big conductance K(+) channels, to block K(+) channels in glioma cells, and antioxidant N-acetyl-l-cysteine (NAC) to inhibit production of intracellular reactive oxygen species (ROS). TEA showed an antiproliferation effect on C6 and U87 glioma cells in a time-dependent manner, which was accompanied by an increased intracellular ROS level. Antioxidant NAC pretreatment reversed TEA-mediated antiproliferation and restored ROS level. TEA treatment also caused significant increases in mRNA and protein levels of tumor-suppressor proteins p53 and p21, and the upregulation was attenuated by pretreatment of NAC. Our results suggest that K(+) channel activity significantly contributes to brain glioma cell proliferation via increasing ROS, and it might be an upstream factor triggering the activation of the p53/p21(Cip1)-dependent signaling pathway, consequently leading to glioma cell cycle arrest.