PMID- 33347611
OWN - NLM
STAT- MEDLINE
DCOM- 20210420
LR  - 20210420
IS  - 1469-7793 (Electronic)
IS  - 0022-3751 (Linking)
VI  - 599
IP  - 6
DP  - 2021 Mar
TI  - Revisiting the Warburg effect: historical dogma versus current understanding.
PG  - 1745-1757
LID - 10.1113/JP278810 [doi]
AB  - Contrary to Warburg's original thesis, accelerated aerobic glycolysis is not a 
      primary, permanent and universal consequence of dysfunctional or impaired 
      mitochondria compensating for poor ATP yield per mole of glucose. Instead, in 
      most tumours the Warburg effect is an essential part of a 'selfish' metabolic 
      reprogramming, which results from the interplay between (normoxic/hypoxic) 
      hypoxia-inducible factor-1 (HIF-1) overexpression, oncogene activation (cMyc, 
      Ras), loss of function of tumour suppressors (mutant p53, mutant phosphatase and 
      tensin homologue (PTEN), microRNAs and sirtuins with suppressor functions), 
      activated (PI3K-Akt-mTORC1, Ras-Raf-MEK-ERK-cMyc, Jak-Stat3) or deactivated 
      (LKB1-AMPK) signalling pathways, components of the tumour microenvironment, and 
      HIF-1 cooperation with epigenetic mechanisms. Molecular and functional processes 
      of the Warburg effect include: (a) considerable acceleration of glycolytic 
      fluxes; (b) adequate ATP generation per unit time to maintain energy homeostasis 
      and electrochemical gradients; (c) backup and diversion of glycolytic 
      intermediates facilitating the biosynthesis of nucleotides, non-essential amino 
      acids, lipids and hexosamines; (d) inhibition of pyruvate entry into 
      mitochondria; (e) excessive formation and accumulation of lactate, which 
      stimulates tumour growth and suppression of anti-tumour immunity - in addition, 
      lactate can serve as an energy source for normoxic cancer cells and drives 
      malignant progression and resistances to conventional therapies; (f) cytosolic 
      lactate being mainly exported through upregulated lactate-proton symporters 
      (MCT4), working together with other H(+) transporters, and carbonic anhydrases 
      (CAII, CAIX), which hydrate CO(2) from oxidative metabolism to form H(+) and 
      bicarbonate; (g) these proton export mechanisms, in concert with poor vascular 
      drainage, being responsible for extracellular acidification, driving malignant 
      progression and resistance to conventional therapies; (h) maintenance of the 
      cellular redox homeostasis and low reactive oxygen species (ROS) formation; and 
      (i) HIF-1 overexpression, mutant p53 and mutant PTEN, which inhibit mitochondrial 
      biogenesis and functions, negatively impacting cellular respiration rate. The 
      glycolytic switch is an early event in oncogenesis and primarily supports cell 
      survival. All in all, the Warburg effect, i.e. aerobic glycolysis in the presence 
      of oxygen and - in principle - functioning mitochondria, constitutes a major 
      driver of the cancer progression machinery, resistance to conventional therapies, 
      and poor patient outcome. However, as evidenced during the last two decades, in a 
      minority of tumours primary mitochondrial defects can play a key role promoting 
      the Warburg effect and tumour progression due to mutations in some Krebs cycle 
      enzymes and mitochondrial ROS overproduction.
CI  - (c) 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd 
      on behalf of The Physiological Society.
FAU - Vaupel, Peter
AU  - Vaupel P
AUID- ORCID: 0000-0003-4238-3188
AD  - Department of Radiation Oncology, Tumour Pathophysiology Group, University 
      Medical Centre, University of Mainz, Germany.
AD  - Department of Radiation Oncology, University Medical Centre, University of 
      Freiburg, Freiburg im Breisgau, Germany.
AD  - German Cancer Consortium (DKTK), Partner Site Freiburg, and German Cancer 
      Research Centre (DKFZ), Heidelberg, Germany.
FAU - Multhoff, Gabriele
AU  - Multhoff G
AD  - Center for Translational Cancer Research, Klinikum rechts der Isar, Technical 
      University Munich, Munich, Germany.
AD  - Department of RadioOncology, Klinikum rechts der Isar, Technical University 
      Munich, Munich, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20210104
PL  - England
TA  - J Physiol
JT  - The Journal of physiology
JID - 0266262
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Glucose
MH  - Glycolysis
MH  - Humans
MH  - *Neoplasms
MH  - *Phosphatidylinositol 3-Kinases
MH  - Tumor Microenvironment
OTO - NOTNLM
OT  - Warburg effect
OT  - aerobic glycolysis
OT  - glycolytic phenotype
OT  - lactate accumulation
OT  - metabolic reprogramming
OT  - tumour acidosis
OT  - tumour glucose metabolism
OT  - tumour mitochondria
EDAT- 2020/12/22 06:00
MHDA- 2021/04/21 06:00
CRDT- 2020/12/21 17:12
PHST- 2020/09/29 00:00 [received]
PHST- 2020/12/03 00:00 [accepted]
PHST- 2020/12/22 06:00 [pubmed]
PHST- 2021/04/21 06:00 [medline]
PHST- 2020/12/21 17:12 [entrez]
AID - 10.1113/JP278810 [doi]
PST - ppublish
SO  - J Physiol. 2021 Mar;599(6):1745-1757. doi: 10.1113/JP278810. Epub 2021 Jan 4.