TY - JOUR
T1 - PIM kinase inhibitor, AZD1208, inhibits protein translation and induces autophagy in primary chronic lymphocytic leukemia cells
AU - Cervantes-Gomez, Fabiola
AU - Stellrecht, Christine M.
AU - Ayres, Mary L.
AU - Keating, Michael J.
AU - Wierda, William G.
AU - Gandhi, Varsha
N1 - Funding Information:
The authors would like to thank Ben Hayes, Mark Hess, Min Fu, and Yuling Chen for coordinating CLL sample distribution and procurement as well as Susan Lerner, Susan Smith and Mark Hess for providing information on patient characteristics and clinical laboratory observations. VG and WGW are members of the CLL Research Consortium. This work was supported in part by Cancer Center Support Grant P50 CA16672, from the National Cancer Institute, Department of Health and Human Services, and a Leukemia and Lymphoma Society Translational Research Award (R6011-14). We thank Jill Delsigne and Diane Hackett from the Department of Scientific Publications at MD Anderson Cancer Center for editorial help in preparing this manuscript.
Funding Information:
VG received funding from AstraZeneca to participate in biomarker studies during the clinical trial for patients with AML and a sponsored research agreement to define biomarkers in AML cell lines. Other authors do not have a conflict of interest.
Publisher Copyright:
© 2019 Impact Journals LLC. All Rights Reserved.
PY - 2019/4/19
Y1 - 2019/4/19
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Autophagy
KW - Chronic lymphocytic leukemia
KW - PIM kinase
KW - Protein translation
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U2 - 10.18632/oncotarget.26876
DO - 10.18632/oncotarget.26876
M3 - Article
C2 - 31073371
AN - SCOPUS:85064964552
SN - 1949-2553
VL - 10
SP - 2793
EP - 2809
JO - Oncotarget
JF - Oncotarget
IS - 29
ER -