Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells

Abstract

IntroductionPim (provirus integration site for Moloney murine leukemia virus) family proteins are highly conserved serine/threonine kinases that have been implicated in cancer progression and the development of resistance to chemotherapeutic agents (for a review, see Shah et al 1 ). Three Pim kinases have been identified to date, Pim-1, -2, and -3, and elevated expression of Pim kinases have been detected in hematologic malignancies and in certain solid tumors. [2][3][4][5] These kinases have similar active sites and lack regulatory domains and thus are constitutively active if expressed. 6 The expression of Pim proteins is via the recruitment of the Janus kinase (JAK) after cytokine receptor activation, resulting in the induction of signal transducer and activator of transcription-driven transcription of PIM genes. 7 Pim kinases have been shown to be involved in several signaling pathways, and the targets identified to date are associated with the regulation of apoptosis, cell-cycle progression, differentiation, transcription, proliferation, and tumorigenesis (reviewed by Amaravadi and Thompson 6 ).PIM1 is a coactivator of MYC, and Pim kinase phosphorylation of histone H3 at serine 10 leads to stimulation of RNA polymerase II binding, which results in increased c-Myc-driven transcription. 8 It is approximated that PIM1 is required for the expression of 20% of total MYC target genes. Other target substrates include proapoptotic Bad protein, which is phosphorylated at multiple sites but predominantly at gatekeeper site Ser112 by all 3 Pim kinases. 9,10 Phosphorylation of Bad leads to its sequestration from the mitochondrial surface to the cytosol by 14-3-3 and subsequent release of antiapoptotic proteins Bcl-X L and Bcl-2. Given the oncogenic nature of Pim kinases, there has been increasing interest in developing Pim kinase inhibitors for the treatment of cancer.Pertaining to cancer biology, increased levels of Pim kinase proteins have been strongly implicated in cell survival and tumorigenesis. Elevated expression of Pim-1 has been demonstrated to induce genomic instability via disruptions in mitotic spindle checkpoints 11 and also functions to protect cells from apoptosis induced by glucocorticoids, 12 genotoxins, 13 or cytokine withdrawal. 14 Pim-1 also has been shown to interact in the p53 pathway via Mdm2. 15 Pim-1 is overexpressed in lymphomas, 16 acute leukemias, 17 and prostate cancer, 5 whereas increased expression of the human PIM2 proto-oncogene is observed in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphomas. 3 Pim-2 also is required to confer rapamycin resistance in hematopoietic cells, 18 and both Pim-1 and Pim-2 have been shown to be required for efficient pre-B-cell transformation by v-Abl oncogene. 19 More recently, Pim-3 was reported to be aberrantly expressed in colon cancer. 20 Taken together, these observations further support the rationale for the development of Pim inhibitors as therapeutic agents for hematologic malignancies. 21 We hypothesized that CLL cells would be responsive...

PIM Kinases Are Essential for Chronic Lymphocytic Leukemia Cell Survival (PIM2/3) and CXCR4-Mediated Microenvironmental Interactions (PIM1)

“…Previous studies have shown an increase in the expression of the PIM2 kinase in CLL cells by using qPCR and intracellular fluorescence-activated cell sorting (FACS) staining [Cohen and colleagues (28); and Chen and colleagues, (41)]. To verify these results in our CLL cohort (Supplementary Table S1), we investigated the expression level of all three PIM kinases at the transcriptional and protein levels.…”

Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma

“…Immunohistochemical staining of tissue microarrays (TMA) reveals that PIM1 is expressed in 87% of mantle cell lymphomas (MCL; Hsi et al, 2008), 76% of chronic lymphocytic leukemia/small lymphocytic lym phoma (CLL/SLL; Chen et al, 2009), and 48 and 42% of dif fuse large B cell lymphoma (DLBCL) and FL, respectively. PIM2 is detected in 42% of DLBCL and between 24% and 30% of FL, MCL, and CLL/SLL (Fig.…”

A pivotal role for Pim-1 kinase in esophageal squamous cell carcinoma involving cell apoptosis induced by reducing Akt phosphorylation

“…More and more evidence has demonstrated that pim-1 kinase plays an important role in tumor progression, including prostatic cancer, laryngeal cancer, lymphocytic leukemia, and head and neck squamous cell carcinomas (14,(24)(25)(26)(27)(28)(29). However, to date, the role of Pim-1 in the development of ESCC has not yet been investigated.…”

“…More and more evidence has demonstrated that Pim-1, a proto-oncogene encoding a serine/threonine protein kinase, plays an essential role in cell survival, cell proliferation, cell differentiation, cell cycle, and cell apoptosis (7)(8)(9)(10)(11)(12)(13)(14), especially in the occurrence and development of tumors (15)(16)(17)(18)(19)(20). Therefore, the rapidly increasing knowledge on the role of the Pim-1 in cancer will hopefully provide useful molecular markers for detection and prognosis of tumor.…”