PMID- 33292639
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210428
IS  - 2049-3002 (Print)
IS  - 2049-3002 (Electronic)
IS  - 2049-3002 (Linking)
VI  - 8
IP  - 1
DP  - 2020 Dec 4
TI  - Protein synthesis inhibitors stimulate MondoA transcriptional activity by driving 
      an accumulation of glucose 6-phosphate.
PG  - 27
LID - 10.1186/s40170-020-00233-6 [doi]
LID - 27
AB  - BACKGROUND: Protein synthesis is regulated by the availability of amino acids, 
      the engagement of growth factor signaling pathways, and adenosine triphosphate 
      (ATP) levels sufficient to support translation. Crosstalk between these inputs is 
      extensive, yet other regulatory mechanisms remain to be characterized. For 
      example, the translation initiation inhibitor rocaglamide A (RocA) induces 
      thioredoxin-interacting protein (TXNIP). TXNIP is a negative regulator of glucose 
      uptake; thus, its induction by RocA links translation to the availability of 
      glucose. MondoA is the principal regulator of glucose-induced transcription, and 
      its activity is triggered by the glycolytic intermediate, glucose 6-phosphate 
      (G6P). MondoA responds to G6P generated by cytoplasmic glucose and mitochondrial 
      ATP (mtATP), suggesting a critical role in the cellular response to these energy 
      sources. TXNIP expression is entirely dependent on MondoA; therefore, we 
      investigated how protein synthesis inhibitors impact its transcriptional 
      activity. METHODS: We investigated how translation regulates MondoA activity 
      using cell line models and loss-of-function approaches. We examined how protein 
      synthesis inhibitors effect gene expression and metabolism using RNA-sequencing 
      and metabolomics, respectively. The biological impact of RocA was evaluated using 
      cell lines and patient-derived xenograft organoid (PDxO) models. RESULTS: We 
      discovered that multiple protein synthesis inhibitors, including RocA, increase 
      TXNIP expression in a manner that depends on MondoA, a functional electron 
      transport chain and mtATP synthesis. Furthermore, RocA and cycloheximide increase 
      mtATP and G6P levels, respectively, and TXNIP induction depends on interactions 
      between the voltage-dependent anion channel (VDAC) and hexokinase (HK), which 
      generates G6P. RocA treatment impacts the regulation of ~ 1200 genes, and ~ 250 
      of those genes are MondoA-dependent. RocA treatment is cytotoxic to triple 
      negative breast cancer (TNBC) cell lines and shows preferential cytotoxicity 
      against estrogen receptor negative (ER-) PDxO breast cancer models. Finally, 
      RocA-driven cytotoxicity is partially dependent on MondoA or TXNIP. CONCLUSIONS: 
      Our data suggest that protein synthesis inhibitors rewire metabolism, resulting 
      in an increase in mtATP and G6P, the latter driving MondoA-dependent 
      transcriptional activity. Further, MondoA is a critical component of the cellular 
      transcriptional response to RocA. Our functional assays suggest that RocA or 
      similar translation inhibitors may show efficacy against ER- breast tumors and 
      that the levels of MondoA and TXNIP should be considered when exploring these 
      potential treatment options.
FAU - Wilde, Blake R
AU  - Wilde BR
AD  - Department of Oncological Sciences, Huntsman Cancer Institute, University of 
      Utah, Salt Lake City, UT, 84112, USA.
AD  - Present Address: Department of Biological Chemistry, David Geffen School of 
      Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
FAU - Kaadige, Mohan R
AU  - Kaadige MR
AD  - Department of Oncological Sciences, Huntsman Cancer Institute, University of 
      Utah, Salt Lake City, UT, 84112, USA.
AD  - Present Address: Translational Genomics Research Institute, Phoenix, AZ, 85004, 
      USA.
FAU - Guillen, Katrin P
AU  - Guillen KP
AD  - Department of Surgery, Huntsman Cancer Institute, University of Utah, Salt Lake 
      City, UT, 84112, USA.
FAU - Butterfield, Andrew
AU  - Butterfield A
AD  - Department of Surgery, Huntsman Cancer Institute, University of Utah, Salt Lake 
      City, UT, 84112, USA.
FAU - Welm, Bryan E
AU  - Welm BE
AD  - Department of Surgery, Huntsman Cancer Institute, University of Utah, Salt Lake 
      City, UT, 84112, USA.
FAU - Ayer, Donald E
AU  - Ayer DE
AD  - Department of Oncological Sciences, Huntsman Cancer Institute, University of 
      Utah, Salt Lake City, UT, 84112, USA. don.ayer@hci.utah.edu.
LA  - eng
GR  - R01 CA222650/CA/NCI NIH HHS/United States
GR  - R01CA222650/CA/NCI NIH HHS/United States
GR  - U54 CA224076/CA/NCI NIH HHS/United States
GR  - P30CA042014-31/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20201204
PL  - England
TA  - Cancer Metab
JT  - Cancer & metabolism
JID - 101607582
PMC - PMC7718662
COIS- The authors declare that they have no competing interests.
EDAT- 2020/12/10 06:00
MHDA- 2020/12/10 06:01
PMCR- 2020/12/04
CRDT- 2020/12/09 05:45
PHST- 2020/07/01 00:00 [received]
PHST- 2020/11/25 00:00 [accepted]
PHST- 2020/12/09 05:45 [entrez]
PHST- 2020/12/10 06:00 [pubmed]
PHST- 2020/12/10 06:01 [medline]
PHST- 2020/12/04 00:00 [pmc-release]
AID - 10.1186/s40170-020-00233-6 [pii]
AID - 233 [pii]
AID - 10.1186/s40170-020-00233-6 [doi]
PST - epublish
SO  - Cancer Metab. 2020 Dec 4;8(1):27. doi: 10.1186/s40170-020-00233-6.