PMID- 26640142
OWN - NLM
STAT- MEDLINE
DCOM- 20170901
LR  - 20221109
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 35
IP  - 30
DP  - 2016 Jul 28
TI  - Targeting glutamine metabolism in multiple myeloma enhances BIM binding to BCL-2 
      eliciting synthetic lethality to venetoclax.
PG  - 3955-64
LID - 10.1038/onc.2015.464 [doi]
AB  - Multiple myeloma (MM) is a plasma cell malignancy that is largely incurable due 
      to development of resistance to therapy-elicited cell death. Nutrients are 
      intricately connected to maintenance of cellular viability in part by inhibition 
      of apoptosis. We were interested to determine if examination of metabolic 
      regulation of BCL-2 proteins may provide insight on alternative routes to engage 
      apoptosis. MM cells are reliant on glucose and glutamine and withdrawal of either 
      nutrient is associated with varying levels of apoptosis. We and others have 
      demonstrated that glucose maintains levels of key resistance-promoting BCL-2 
      family member, myeloid cell leukemic factor 1 (MCL-1). Cells continuing to 
      survive in the absence of glucose or glutamine were found to maintain expression 
      of MCL-1 but importantly induce pro-apoptotic BIM expression. One potential 
      mechanism for continued survival despite induction of BIM could be due to binding 
      and sequestration of BIM to alternate pro-survival BCL-2 members. Our 
      investigation revealed that cells surviving glutamine withdrawal in particular, 
      enhance expression and binding of BIM to BCL-2, consequently sensitizing these 
      cells to the BH3 mimetic venetoclax. Glutamine deprivation-driven sensitization 
      to venetoclax can be reversed by metabolic supplementation with TCA cycle 
      intermediate alpha-ketoglutarate. Inhibition of glucose metabolism with the GLUT4 
      inhibitor ritonavir elicits variable cytotoxicity in MM that is marginally 
      enhanced with venetoclax treatment, however, targeting glutamine metabolism with 
      6-diazo-5-oxo-l-norleucine uniformly sensitized MM cell lines and 
      relapse/refractory patient samples to venetoclax. Our studies reveal a potent 
      therapeutic strategy of metabolically driven synthetic lethality involving 
      targeting glutamine metabolism for sensitization to venetoclax in MM.
FAU - Bajpai, R
AU  - Bajpai R
AD  - Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory 
      University School of Medicine, Atlanta, GA, USA.
FAU - Matulis, S M
AU  - Matulis SM
AD  - Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory 
      University School of Medicine, Atlanta, GA, USA.
FAU - Wei, C
AU  - Wei C
AD  - Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory 
      University School of Medicine, Atlanta, GA, USA.
FAU - Nooka, A K
AU  - Nooka AK
AD  - Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory 
      University School of Medicine, Atlanta, GA, USA.
FAU - Von Hollen, H E
AU  - Von Hollen HE
AD  - Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory 
      University School of Medicine, Atlanta, GA, USA.
FAU - Lonial, S
AU  - Lonial S
AD  - Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory 
      University School of Medicine, Atlanta, GA, USA.
FAU - Boise, L H
AU  - Boise LH
AD  - Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory 
      University School of Medicine, Atlanta, GA, USA.
FAU - Shanmugam, M
AU  - Shanmugam M
AD  - Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory 
      University School of Medicine, Atlanta, GA, USA.
LA  - eng
GR  - P30 CA138292/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20151207
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Bcl-2-Like Protein 11)
RN  - 0 (Bridged Bicyclo Compounds, Heterocyclic)
RN  - 0 (Glucose Transporter Type 4)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Sulfonamides)
RN  - 0RH81L854J (Glutamine)
RN  - N54AIC43PW (venetoclax)
RN  - O3J8G9O825 (Ritonavir)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Bcl-2-Like Protein 11/*metabolism
MH  - Bridged Bicyclo Compounds, Heterocyclic/*pharmacology
MH  - Cell Line, Tumor
MH  - Glucose Transporter Type 4/antagonists & inhibitors
MH  - Glutamine/*metabolism
MH  - Humans
MH  - Multiple Myeloma/*drug therapy/metabolism
MH  - Proto-Oncogene Proteins c-bcl-2/*metabolism
MH  - Ritonavir/pharmacology
MH  - Sulfonamides/*pharmacology
PMC - PMC5025767
MID - NIHMS734930
EDAT- 2015/12/08 06:00
MHDA- 2017/09/02 06:00
PMCR- 2016/06/07
CRDT- 2015/12/08 06:00
PHST- 2015/08/17 00:00 [received]
PHST- 2015/10/09 00:00 [revised]
PHST- 2015/10/30 00:00 [accepted]
PHST- 2015/12/08 06:00 [entrez]
PHST- 2015/12/08 06:00 [pubmed]
PHST- 2017/09/02 06:00 [medline]
PHST- 2016/06/07 00:00 [pmc-release]
AID - onc2015464 [pii]
AID - 10.1038/onc.2015.464 [doi]
PST - ppublish
SO  - Oncogene. 2016 Jul 28;35(30):3955-64. doi: 10.1038/onc.2015.464. Epub 2015 Dec 7.