Abstract
Pan proviral integrations of Moloney virus (PIM) inhibition in multiple myeloma (MM) results in reduced cell viability in tested human-derived MM cell lines and reduces tumor burden in xenograft mouse models, making PIMs important therapeutic targets for the disease. PIM kinase inhibitors are currently being tested clinically in MM. We sought to elucidate the role of the various PIMs in MM. Our data demonstrate that Pim2 has a significant role in MM cell cytotoxicity. Our data provide evidence for a novel role for Pim2 in the regulation of the DNA damage response (DDR). Knockdown of Pim2 upregulates several downstream DDR markers, mimicking the effects of doxorubicin (Dox) treatment of MM cells, and suggesting a role for the kinase as a negative regulator of this pathway. Dox-induced DNA damage results in a decrease in Pim2 levels, placing the kinase directly downstream of the site of Dox-DNA binding. Overexpression of Pim2 confers a slight survival advantage against Dox through antiapoptotic activity, further underscoring its relevance in the DDR pathway. These data provide insights into a novel mechanism of PIM kinase activity and provide the framework for designing therapeutic approaches in MM.
Highlights
The proviral integrations of Moloney virus (PIM) kinases are serinethreonine kinases that have recently been shown to have a multitudinous and integral role in the evolution and progression of many hematological malignancies.[1,2] In multiple myeloma (MM) they occupy an important stratum of kinases that promote cancer cell proliferation and protect from apoptosis.[3]
The results of this study illuminate a dynamic nature of activity for PIM2, and further support its importance in MM cell survival
The PIM kinases are upregulated in the CD138 + fraction of patient bone marrow, and PIM2 was seen to be the most highly expressed of the three kinases within the cancer compartment
Summary
The proviral integrations of Moloney virus (PIM) kinases are serinethreonine kinases that have recently been shown to have a multitudinous and integral role in the evolution and progression of many hematological malignancies.[1,2] In multiple myeloma (MM) they occupy an important stratum of kinases that promote cancer cell proliferation and protect from apoptosis.[3] The PIM kinase family is composed of three serine-threonine kinase isoforms; PIM1, 2 and 3, which are constitutively active in cancer cells.[4] Translation of the PIM kinases is promoted by cytokinemediated activation of the JAK-STAT (Janus kinase/signal transducers and activators of transcription) and NF-κB (nuclear factor-κB) pathways, causing an increase in PIM expression levels in MM cells when in coculture with the bone marrow stromal cell (BMSC) compartment.[3] Interleukin-6 (IL-6) is secreted by BMSCs into the microenvironment and activates the STAT3 pathway in MM cells to promote PIM transcription.[3] In MM cells, the PIMs act as prosurvival factors to phosphorylate Bcl-2-associated agonist of cell death (BAD) and prevent apoptosis.[5] PIM2 further promotes cell proliferation by phosphorylating the active suppressant of mammalian target of rapamycin complex 1 activity, TSC2, and causing it to dissociate with mammalian target of rapamycin complex 1.6 PIM inhibition results in a decrease in phosphorylated
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