Functional and molecular interactions between ERK and CHK2 in diffuse large B-cell lymphoma.

Distinct oncogenic signalling cascades have been associated with non-Hodgkin lymphoma. ERK1/2 signalling elicits both transcriptional and post-transcriptional effects through phosphorylation of numerous substrates. Here we report a novel molecular relationship between ERK1/2 and CHK2, a protein kinase that is a key mediator of the DNA damage checkpoint that responds to DNA double-strand breaks. Our studies are the first to demonstrate the co-localization and overexpression of ERK1/2 and CHK2 in diffuse large B-cell lymphoma (DLBCL). The physical interaction between ERK and CHK2 was highly dependent on phosphorylated Thr 68 of CHK2. Concurrent administration of an ERK inhibitor enhances the antitumour activity of CHK2 inhibition in both a human DLBCL xenograft model as well as primary human DLBCL cells. Our data suggest a functional interaction between ERK and CHK2 and support the potential combined therapeutic targeting of ERK and CHK2 in human DLBCL.

Alcohol consumption and decreased risk of non-Hodgkin lymphoma: role of mTOR dysfunction.

Several epidemiologic studies support the emerging paradigm that current alcohol consumers have decreased risk of most types of non-Hodgkin lymphoma. The observed lower risk among people who drank alcohol does not seem to vary with beverage type. The mechanisms accounting for alcohol-induced decrease in the incidence of lymphomas remain largely unknown. We demonstrate that low-dose chronic exposure to ethanol inhibits mammalian target of rapamycin (mTOR) C1 complex formation, resulting in decreased phosphorylation events involved in mTOR pathway signaling in a lymphoid-tissue specific manner. These changes in mTOR signaling lead to a decrease in eIF4E associated with the translation initiation complex and a repression of global cap-dependent synthesis in both lymphoma cell lines and normal donor lymphocytes. We show that chronic exposure of ethanol at physiologically relevant concentrations in a xenograft model results in a striking inhibition of lymphoma growth. Our data support a paradigm in which chronic ethanol exposure inhibits mTOR signaling in lymphocytes with a significant repression of cap-dependent translation, reducing the tumorigenic capacity of non-Hodgkin lymphoma in a human xenograft model. The ethanol-mediated repression of mTOR signaling coupled with decreased in vivo lymphoma growth underscore the critical role of mTOR signaling and translation in lymphoma.

Targeted suppression of MCT-1 attenuates the malignant phenotype through a translational mechanism.

The MCT-1 oncogene, highly expressed in a subset of non-Hodgkin's lymphomas interacts with the cap complex through its PUA domain. MCT-1 recruits DENR, a SUI1 motif containing protein that promotes translation initiation of cancer-related mRNAs. We reasoned that a PUA-domain mutant protein would repress MCT-1 function and attenuate the malignant phenotype. Human lymphoma cell lines expressing the PUA-domain mutant protein demonstrated reduced anchorage-independent growth and increased susceptibility to apoptosis. Significantly, we identified an altered translational profile in cells expressing the mutant protein. These data further buttress the role of the MCT-1 in lymphomagenesis and support the development of novel therapeutic strategies targeting MCT-1.