DRR regulates AKT activation to drive brain cancer invasion.

Glioblastoma (GBM) is the most common and invasive adult brain cancer. The rapid invasion of cancer cells into the normal brain is a major cause of treatment failure, yet the mechanisms that regulate this process are poorly understood. We have identified a novel mechanism of brain cancer invasion. We show that downregulated in renal cell carcinoma (DRR), which is newly expressed in invasive gliomas, recruits AKT to focal adhesions. This DRR- induced pathological relocalization of AKT bypasses commonly altered upstream signaling events and leads to AKT activation and invasion. We also developed an oligonucleotide therapeutic that reduces DRR expression and prevents glioma invasion in an in vivo preclinical model of the disease. Our findings identify DRR as a novel GBM target and show that oligonucleotides targeting DRR is a novel therapeutic approach for the treatment of DRR-positive GBMs.

DRR drives brain cancer invasion by regulating cytoskeletal-focal adhesion dynamics.

Malignant glioma invasion is a primary cause of brain cancer treatment failure, yet the molecular mechanisms underlying its regulation remain elusive. We developed a novel functional-screening strategy and identified downregulated in renal cell carcinoma (DRR) as a regulator of invasion. We show that DRR drives invasion in vitro and in vivo. We found that while DRR is not expressed in normal glial cells, it is highly expressed in the invasive component of gliomas. Exploring underlying mechanisms, we show that DRR associates with and organizes the actin and microtubular cytoskeletons and that these associations are essential for focal adhesion (FA) disassembly and cell invasion. These findings identify DRR as a new cytoskeletal crosslinker that regulates FA dynamics and cell movement.

Mechanism of asynchronous Ca(2+) waves underlying agonist-induced contraction in the rat basilar artery.

BACKGROUND AND PURPOSE: Uridine 5'-triphosphate (UTP) is a potent vasoconstrictor of cerebral arteries and induces Ca(2+) waves in vascular smooth muscle cells (VSMCs). This study aimed to determine the mechanisms underlying UTP-induced Ca(2+) waves in VSMCs of the rat basilar artery. EXPERIMENTAL APPROACH: Isometric force and intracellular Ca(2+) ([Ca(2+)](i)) were measured in endothelium-denuded rat basilar artery using wire myography and confocal microscopy respectively. KEY RESULTS: Uridine 5'-triphosphate (0.1-1000 micromol.L(-1)) concentration-dependently induced tonic contraction (pEC(50) = 4.34 +/- 0.13), associated with sustained repetitive oscillations in [Ca(2+)](i) propagating along the length of the VSMCs as asynchronized Ca(2+) waves. Inhibition of Ca(2+) reuptake in sarcoplasmic reticulum (SR) by cyclopiazonic acid abolished the Ca(2+) waves and resulted in a dramatic drop in tonic contraction. Nifedipine reduced the frequency of Ca(2+) waves by 40% and tonic contraction by 52%, and the nifedipine-insensitive component was abolished by SKF-96365, an inhibitor of receptor- and store-operated channels, and KB-R7943, an inhibitor of reverse-mode Na(+)/Ca(2+) exchange. Ongoing Ca(2+) waves and tonic contraction were also abolished after blockade of inositol-1,4,5-triphosphate-sensitive receptors by 2-aminoethoxydiphenylborate, but not by high concentrations of ryanodine or tetracaine. However, depletion of ryanodine-sensitive SR Ca(2+) stores prior to UTP stimulation prevented Ca(2+) waves. CONCLUSIONS AND IMPLICATIONS: Uridine 5'-triphosphate-induced Ca(2+) waves may underlie tonic contraction and appear to be produced by repetitive cycles of regenerative Ca(2+) release from the SR through inositol-1,4,5-triphosphate-sensitive receptors. Maintenance of Ca(2+) waves requires SR Ca(2+) reuptake from Ca(2+) entry across the plasma membrane via L-type Ca(2+) channels, receptor- and store-operated channels, and reverse-mode Na(+)/Ca(2+) exchange.