PMID- 30190422
OWN - NLM
STAT- MEDLINE
DCOM- 20190910
LR  - 20240405
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 17
IP  - 12
DP  - 2018 Dec
TI  - Mechanisms Behind Resistance to PI3K Inhibitor Treatment Induced by the PIM 
      Kinase.
PG  - 2710-2721
LID - 10.1158/1535-7163.MCT-18-0374 [doi]
AB  - Cancer resistance to PI3K inhibitor therapy can be in part mediated by increases 
      in the PIM1 kinase. However, the exact mechanism by which PIM kinase promotes 
      tumor cell resistance is unknown. Our study unveils the pivotal control of redox 
      signaling by PIM kinases as a driver of this resistance mechanism. PIM1 kinase 
      functions to decrease cellular ROS levels by enhancing nuclear factor erythroid 
      2-related factor 2 (NRF2)/antioxidant response element activity. PIM prevents 
      cell death induced by PI3K-AKT-inhibitory drugs through a noncanonical mechanism 
      of NRF2 ubiquitination and degradation and translational control of NRF2 protein 
      levels through modulation of eIF4B and mTORC1 activity. Importantly, PIM also 
      controls NAD(P)H production by increasing glucose flux through the pentose 
      phosphate shunt decreasing ROS production, and thereby diminishing the 
      cytotoxicity of PI3K-AKT inhibitors. Treatment with PIM kinase inhibitors 
      reverses this resistance phenotype, making tumors increasingly susceptible to 
      small-molecule therapeutics, which block the PI3K-AKT pathway.
CI  - (c)2018 American Association for Cancer Research.
FAU - Song, Jin H
AU  - Song JH
AUID- ORCID: 0000-0002-0123-2909
AD  - Department of Cellular and Molecular Medicine, University of Arizona, Tucson, 
      Arizona. jinsong@email.arizona.edu akraft@uacc.arizona.edu.
AD  - University of Arizona Cancer Center, Tucson, Arizona.
FAU - Singh, Neha
AU  - Singh N
AD  - University of Arizona Cancer Center, Tucson, Arizona.
FAU - Luevano, Libia A
AU  - Luevano LA
AD  - University of Arizona Cancer Center, Tucson, Arizona.
FAU - Padi, Sathish K R
AU  - Padi SKR
AD  - University of Arizona Cancer Center, Tucson, Arizona.
FAU - Okumura, Koichi
AU  - Okumura K
AD  - Department of Physiology, University of Arizona, Tucson, Arizona.
FAU - Olive, Virginie
AU  - Olive V
AD  - Department of Medicine, University of Arizona, Tucson, Arizona.
FAU - Black, Stephen M
AU  - Black SM
AD  - Department of Physiology, University of Arizona, Tucson, Arizona.
AD  - Department of Medicine, University of Arizona, Tucson, Arizona.
FAU - Warfel, Noel A
AU  - Warfel NA
AD  - Department of Cellular and Molecular Medicine, University of Arizona, Tucson, 
      Arizona.
AD  - University of Arizona Cancer Center, Tucson, Arizona.
FAU - Goodrich, David W
AU  - Goodrich DW
AUID- ORCID: 0000-0002-1021-1827
AD  - Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, New 
      York, New York.
FAU - Kraft, Andrew S
AU  - Kraft AS
AD  - University of Arizona Cancer Center, Tucson, Arizona. jinsong@email.arizona.edu 
      akraft@uacc.arizona.edu.
AD  - Department of Medicine, University of Arizona, Tucson, Arizona.
LA  - eng
GR  - R01 CA173200/CA/NCI NIH HHS/United States
GR  - P30 CA023074/CA/NCI NIH HHS/United States
GR  - P01 HL134610/HL/NHLBI NIH HHS/United States
GR  - P30 ES006694/ES/NIEHS NIH HHS/United States
GR  - R01 CA207757/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20180906
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-pim-1)
RN  - EC 2.7.11.1 (proto-oncogene proteins pim)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - *Drug Resistance, Neoplasm/drug effects
MH  - Drug Synergism
MH  - Glutathione/metabolism
MH  - Humans
MH  - Male
MH  - Mice, SCID
MH  - NF-E2-Related Factor 2/metabolism
MH  - Oxidation-Reduction
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Protein Stability/drug effects
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/metabolism
MH  - Proto-Oncogene Proteins c-pim-1/*metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Ubiquitination/drug effects
MH  - Up-Regulation/drug effects
PMC - PMC6279580
MID - NIHMS1506054
COIS- Disclosure of Potential Conflicts of Interest Research. The authors disclose no 
      competing interest.
EDAT- 2018/09/08 06:00
MHDA- 2019/09/11 06:00
PMCR- 2019/12/01
CRDT- 2018/09/08 06:00
PHST- 2018/04/10 00:00 [received]
PHST- 2018/05/27 00:00 [revised]
PHST- 2018/08/30 00:00 [accepted]
PHST- 2018/09/08 06:00 [pubmed]
PHST- 2019/09/11 06:00 [medline]
PHST- 2018/09/08 06:00 [entrez]
PHST- 2019/12/01 00:00 [pmc-release]
AID - 1535-7163.MCT-18-0374 [pii]
AID - 10.1158/1535-7163.MCT-18-0374 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2018 Dec;17(12):2710-2721. doi: 10.1158/1535-7163.MCT-18-0374. 
      Epub 2018 Sep 6.