Abstract
The PIM1, PIM2, and PIM3 serine/threonine kinases play a role in the proliferation and survival of cancer cells. Mice lacking these three kinases were viable. Further, in human hematological malignancies, these proteins are overexpressed making them suitable targets. Several small molecule inhibitors against this enzyme were synthesized and tested. AZD1208, an orally available small-molecule drug, inhibits all three PIM kinases at a low nanomolar range. AZD1208 has been tested in clinical trials for patients with solid tumors and hematological malignancies, especially acute myelogenous leukemia. The present study evaluated the efficacy and biological actions of AZD1208 in chronic lymphocytic leukemia (CLL) cells. CLL cells had higher levels of PIM2 protein and mRNAs than did normal lymphocytes from healthy donors. Treatment of CLL lymphocytes with AZD1208 resulted in modest cell death, whereas practically no cytotoxicity was observed in healthy lymphocytes. To determine the mechanism by which AZD1208 inhibits PIM kinase function, we evaluated PIM kinase pathway and downstream substrates. Because peripheral blood CLL cells are replicationally quiescent, we analyzed substrates involved in apoptosis, transcription, and translation but not cell cycle targets. AZD1208 inhibited protein translation by decreasing phosphorylation levels of 4E-binding protein 1 (4E-BP1). AZD1208 induced autophagy in replicationally-quiescent CLL cells, which is consistent with protein translation inhibition. These data suggest that AZD1208 may elicit cytotoxicity in CLL cells through inhibiting translation and autophagy induction.
Highlights
Identification of proviral integration site for Moloney murine leukemia virus-induced lymphoma resulted in discovery of a proto-oncogene, termed PIM which was transcriptionally activated due to this insertion [1]
There were 2 bands observed for PIM2, and PIM2 and PIM3 expression levels were consistently higher in the chronic lymphocytic leukemia (CLL) lymphocytes than in the healthy lymphocytes
PIM1 and PIM3 mRNA levels were similar in lymphocytes from healthy donors and CLL patient samples, but PIM3 levels were lower than PIM1 in both healthy donors and patients
Summary
Identification of proviral integration site for Moloney murine leukemia virus-induced lymphoma resulted in discovery of a proto-oncogene, termed PIM which was transcriptionally activated due to this insertion [1]. After PIM-1, two additional isoforms of PIM kinases have been identified; PIM2 and PIM3 which are able to phosphorylate numerous substrates with regulatory functions in several cellular processes [2] These kinases are constitutively active and are early responder genes to growth factors and cytokines. PIM’s pivotal role for cancer in general and hematological malignancies in particular became apparent as these proteins are overexpressed in malignant cells These kinases are required for the efficient proliferation of peripheral T lymphocytes [3] and are needed for Abelson murine leukemia viral oncogene–mediated transformation www.oncotarget.com of pre-B cells [4] or Epstein-Barr virus infection [5]. These data elucidate the role of PIM kinases in B-cell malignancies and use of PIM kinase inhibitors for these neoplasms
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