title: Pim2 is important for regulating DNA damage response in multiple myeloma cells.
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.
authors: Massachusetts General Hospital Cancer Center, MGH Cancer Center, Harvard Medical School, Boston, MA, USA.
authors: J
authors: J
authors: Ramachandran
authors: Massachusetts General Hospital Cancer Center, MGH Cancer Center, Harvard Medical School, Boston, MA, USA.
authors: L
authors: L
authors: Santo
authors: Massachusetts General Hospital Cancer Center, MGH Cancer Center, Harvard Medical School, Boston, MA, USA.
authors: K T
authors: KT
authors: Siu
authors: Massachusetts General Hospital Cancer Center, MGH Cancer Center, Harvard Medical School, Boston, MA, USA.
authors: C
authors: C
authors: Panaroni
authors: Massachusetts General Hospital Cancer Center, MGH Cancer Center, Harvard Medical School, Boston, MA, USA.
authors: N
authors: N
authors: Raje
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C490587:PIM2 protein, human; D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases