The Tumor Suppressor Nm23-H1 Blocks Activity of the Oncogene Dbl-1

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  2. The Tumor Suppressor Nm23-H1 Blocks Activity of the Oncogene Dbl-1
  3. How a Neurotransmitter Regulates Cancer

Murakami et al., pp. 500–510

Nm23-H1 is a master regulator of tumor migration and metastasis. Highly metastatic and invasive tumors express low levels of Nm23-H1 transcripts, suggesting that the protein functions as a negative regulator of cell migration. Murakami and colleagues searched for mechanisms of the tumor-suppressive activity of Nm23-H1. Using a yeast two-hybrid system, they identified Dbl-1 as a novel interaction partner. Dbl-1 is a guanine exchange factor that activates the RhoGTPase Cdc42, a factor involved in cytoskeletal reorganization, cell motility and cell adhesion. Importantly, Dbl-1 is an oncoprotein expressed in diffuse B-cell lymphoma and generated from the proto-oncogene pDbl.

The authors performed a detailed set of experiments to show that Nm23-H1 and Dbl-1 interact and partially colocalize in cells. Nm23-H1 is primarily localized in the cytoplasm but colocalizes with Dbl-1 at the plasma membrane where it inhibits Dbl-1 activity on Cdc42. Dbl-1 normally activates Cdc42 by exchanging the bound GDP for GTP. Overexpression of Nm23-H1 interferes with the ability of DBl-1 to load GTP onto Cdc42, thereby modulating membrane ruffling and focal adhesion activities in cancer cells.

The study identifies a novel link between the tumor suppressor activity of Nm23-H1 and cellular molecules in control of cytoskeletal rearrangements. Harnessing the negative effect of Nm23-H1 on Dbl-1/Cdc42 activity may represent a novel strategy to limit invasion of diffuse large B-cell lymphomas.1.

Nm23-H1 interacts with Dbl-1 at the plasma membrane and inhibits the activity of Dbl-1 on Cdc42. Expression constructs for Nm23-H1 (green) and Dbl-1 (red) were transfected into 293T cells and analyzed by confocal microscopy. Nuclei of cells are shown in blue (DAPI).

How a Neurotransmitter Regulates Cancer

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  2. The Tumor Suppressor Nm23-H1 Blocks Activity of the Oncogene Dbl-1
  3. How a Neurotransmitter Regulates Cancer

Asada et al., pp. 511–518

Patients with schizophrenia develop less cancer than the general population. This decrease is striking because risk factors such as smoking and drinking are more frequent in this patient population. Asada and colleagues address this conundrum in a mouse model of schizophrenia. Mice lacking the dopamine transporter DAT were injected subcutaneously with Lewis lung carcinoma cells to study tumor development in the context of hyperdopaminergic neurotransmission resembling schizophrenia. DAT controls the uptake of dopamine into presynaptic terminals, and its loss leads to abnormal behavior and neuroendocrinal dysfunctions.

Tumors in DAT-/- mice were significantly smaller than in heterozygous or normal littermates. In addition, the number of tumor-associated vessels was decreased, pointing towards a connection between dopaminergic neurotransmission and tumor angiogenesis. When the authors treated normal mice injected with Lewis lung carcinoma cells with drugs modulating the dopaminergic system, they found that a selective inhibitor of the dopamine D1 receptor reduced tumor growth. Both D1 and D2 receptors are downregulated in DAT-/- mice.

The authors propose that reduced signaling through the D1 receptor inhibits dopamine-induced VEGF receptor 2 phosphorylation and reduces tumor angiogenesis in DAT-/- mice. In support of this model, they show that tumor growth is slowed in mice lacking the D1 receptor.

The study reveals an interesting connection between the neurotransmitter dopamine and tumor angiogenesis and identifies the dopamine D1 receptor as a potential target for cancer therapy.