The Abelson (ABL) family of nonreceptor tyrosine kinases, ABL1 and ABL2, transduces diverse extracellular signals to protein networks that control proliferation, survival, migration, and invasion. ABL1 was first identified as an oncogene required for the development of leukemias initiated by retroviruses or chromosome translocations. The demonstration that small molecule ABL kinase inhibitors effectively treat chronic myeloid leukemia opened the door to the era of targeted cancer therapies. Recent reports have uncovered roles for ABL kinases in solid tumors. Enhanced ABL expression and activation in some solid tumors, together with altered cell polarity, invasion or growth induced by activated ABL kinases, suggest that drugs targeting these kinases may have utility in treating selected solid tumors.

The Abl tyrosine kinases, Abl and Arg, play a role in the regulation of the actin cytoskeleton by modulating cell-cell adhesion and cell motility. Deregulation of both the actin cytoskeleton and Abl kinases have been implicated in cancers. Abl kinase activity is elevated in a number of metastatic cancers and these kinases are activated downstream of several oncogenic growth factor receptor signaling pathways. However, the role of Abl kinases in regulation of the actin cytoskeleton during tumor progression and invasion remains elusive. Here we identify the Abl kinases as essential regulators of invadopodia assembly and function. We show that Abl kinases are activated downstream of the chemokine receptor, CXCR4, and are required for cancer cell invasion and matrix degradation induced by SDF1␣, serum growth factors, and activated Src kinase. Moreover, Abl kinases are readily detected at invadopodia assembly sites and their inhibition prevents the assembly of actin and cortactin into organized invadopodia structures. We show that active Abl kinases form complexes with membrane type-1 matrix metalloproteinase (MT1-MMP), a critical invadopodia component required for matrix degradation. Further, loss of Abl kinase signaling induces internalization of MT1-MMP from the cell surface, promotes its accumulation in the perinuclear compartment and inhibits MT1-MMP tyrosine phosphorylation. Our findings reveal that Abl kinase signaling plays a critical role in invadopodia formation and function, and have far-reaching implications for the treatment of metastatic carcinomas.Podosomes and invadopodia are specialized protrusive structures consisting of a core assembly of F-actin-and actinbinding proteins that form on the ventral surface of migratory and invading cells. These structures are observed in physiological and pathological processes that involve remodeling of the extracellular environment and are found in endothelial cells during extracellular matrix (ECM) 5 degradation (1), transmigrating monocytic cells (2, 3), osteoclasts during bone reabsorption (4), and cancer cells during invasion and metastasis (5). Although podosomes and invadopodia are structurally distinct, they share many common features such as the enrichment of integrins, actin regulatory proteins, matrix metalloproteinases (MMPs), and tyrosine kinases (6 -8).Carcinoma cells utilize invadopodia to degrade the ECM during tumor invasion and metastasis (8). Invadopodia assembly occurs through sequential steps that begin with the assembly of precursor structures containing actin, cortactin, Tsk5, N-WASP, and other actin regulatory proteins, and progress into mature structures with matrix degradation activity (9). Invadopodia were first described in cells transformed with oncogenic v-Src (10), and endogenous Src kinases have been shown to promote podosome/invadopodia formation in response to growth factors and chemokines (1, 11-13). Src phosphorylates several invadopodia components including cortactin, N-WASP, and Tsk5/FISH (14). Cortactin regulates the formation ...

Glioblastomas are notorious for their resistance to ionizing radiation (IR) and chemotherapy. We hypothesize that this resistance to IR is due, in part, to alterations in antioxidant enzymes. Here, we show that rat and human glioma cells overexpress the antioxidant enzyme, peroxiredoxin II (Prx II). Glioma cells in which Prx II is decreased using shRNA exhibit increased hyper-oxidization of the remaining cellular Prxs suggesting that the redox environment is more oxidizing. Of interest, decreasing Prx II does not alter other antioxidant enzymes (i.e. catalase, GPx, Prx I, Prx III, CuZnSOD, and MnSOD). Analysis of the redox environment revealed that decreasing Prx II increased intracellular ROS in 36B10 cells; extracellular levels of H2O2 were also increased in both C6 and 36B10 cells. Treatment with H2O2 led to a further elevation in intracellular ROS in cells where Prx II was decreased. Decreasing Prx II expression in glioma cells also reduced clonogenic cell survival following exposure to IR and H2O2. Furthermore, lowering Prx II expression decreased intracellular glutathione and resulted in a significant decline in glutathione reductase activity, suggesting a possible mechanism for the observed increased sensitivity to oxidative insults. Additionally, decreasing Prx II expression increased cell cycle doubling times with less cells distributed to S-phase in C6 glioma cells and more cells redistributed to the most radiosensitive phase of cell cycle, G2/M, in 36B10 glioma cells. These findings support the hypothesis that inhibiting Prx II sensitizes glioma cells to oxidative stress presenting Prxs as potential therapeutic targets.

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