PMID- 35078427
OWN - NLM
STAT- MEDLINE
DCOM- 20220303
LR  - 20220303
IS  - 1471-2407 (Electronic)
IS  - 1471-2407 (Linking)
VI  - 22
IP  - 1
DP  - 2022 Jan 25
TI  - The mixed blessing of AMPK signaling in Cancer treatments.
PG  - 105
LID - 10.1186/s12885-022-09211-1 [doi]
LID - 105
AB  - BACKGROUND: Nutrient acquisition and metabolism pathways are altered in cancer 
      cells to meet bioenergetic and biosynthetic demands. A major regulator of 
      cellular metabolism and energy homeostasis, in normal and cancer cells, is 
      AMP-activated protein kinase (AMPK). AMPK influences cell growth via its 
      modulation of the mechanistic target of Rapamycin (mTOR) pathway, specifically, 
      by inhibiting mTOR complex mTORC1, which facilitates cell proliferation, and by 
      activating mTORC2 and cell survival. Given its conflicting roles, the effects of 
      AMPK activation in cancer can be counter intuitive. Prior to the establishment of 
      cancer, AMPK acts as a tumor suppressor. However, following the onset of cancer, 
      AMPK has been shown to either suppress or promote cancer, depending on cell type 
      or state. METHODS: To unravel the controversial roles of AMPK in cancer, we 
      developed a computational model to simulate the effects of pharmacological 
      maneuvers that target key metabolic signalling nodes, with a specific focus on 
      AMPK, mTORC, and their modulators. Specifically, we constructed an ordinary 
      differential equation-based mechanistic model of AMPK-mTORC signaling, and 
      parametrized the model based on existing experimental data. RESULTS: Model 
      simulations were conducted to yield the following predictions: (i) increasing 
      AMPK activity has opposite effects on mTORC depending on the nutrient 
      availability; (ii) indirect inhibition of AMPK activity through inhibition of 
      sirtuin 1 (SIRT1) only has an effect on mTORC activity under conditions of low 
      nutrient availability; (iii) the balance between cell proliferation and survival 
      exhibits an intricate dependence on DEP domain-containing mTOR-interacting 
      protein (DEPTOR) abundance and AMPK activity; (iv) simultaneous direct inhibition 
      of mTORC2 and activation of AMPK is a potential strategy for suppressing both 
      cell survival and proliferation. CONCLUSIONS: Taken together, model simulations 
      clarify the competing effects and the roles of key metabolic signalling pathways 
      in tumorigenesis, which may yield insights on innovative therapeutic strategies.
CI  - (c) 2022. The Author(s).
FAU - Sadria, Mehrshad
AU  - Sadria M
AD  - Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, 
      Canada. msadria@uwaterloo.ca.
FAU - Seo, Deokhwa
AU  - Seo D
AD  - Faculty of Engineering, University of Waterloo, Waterloo, Ontario, Canada.
FAU - Layton, Anita T
AU  - Layton AT
AD  - Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, 
      Canada.
AD  - Cheriton School of Computer Science, Department of Biology, and the School of 
      Pharmacy, University of Waterloo, Waterloo, Ontario, Canada.
LA  - eng
PT  - Journal Article
DEP - 20220125
PL  - England
TA  - BMC Cancer
JT  - BMC cancer
JID - 100967800
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - EC 2.7.1.1 (DEPTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Animals
MH  - Carcinogenesis/*metabolism
MH  - Cell Growth Processes
MH  - Cell Proliferation
MH  - Computer Simulation
MH  - Energy Metabolism
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/metabolism
MH  - Neoplasms/*enzymology
MH  - Signal Transduction/*physiology
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC8786626
OTO - NOTNLM
OT  - AMPK
OT  - Cancer
OT  - Dynamical system
OT  - Metabolism
OT  - mTORC
COIS- The authors declare that they have no competing interests
EDAT- 2022/01/27 06:00
MHDA- 2022/03/04 06:00
PMCR- 2022/01/25
CRDT- 2022/01/26 05:26
PHST- 2021/09/06 00:00 [received]
PHST- 2022/01/17 00:00 [accepted]
PHST- 2022/01/26 05:26 [entrez]
PHST- 2022/01/27 06:00 [pubmed]
PHST- 2022/03/04 06:00 [medline]
PHST- 2022/01/25 00:00 [pmc-release]
AID - 10.1186/s12885-022-09211-1 [pii]
AID - 9211 [pii]
AID - 10.1186/s12885-022-09211-1 [doi]
PST - epublish
SO  - BMC Cancer. 2022 Jan 25;22(1):105. doi: 10.1186/s12885-022-09211-1.