AMPK and HIF signaling pathways regulate both longevity and cancer growth: the good news and the bad news about survival mechanisms.
The AMP-activated protein kinase (AMPK) and hypoxia-inducible factor (HIF) signaling pathways are evolutionarily-conserved survival mechanisms responding to two fundamental stresses, energy deficiency and/or oxygen deprivation. The AMPK and HIF pathways regulate the function of a survival network with several transcription factors, e.g. FOXO, NF-κB, NRF2, and p53, as well as with protein kinases and other factors, such as mTOR, ULK1, HDAC5, and SIRT1. Given that AMPK and HIF activation can enhance not only healthspan and lifespan but also cancer growth in a context-dependent manner; it seems that cancer cells can hijack certain survival factors to maintain their growth in harsh conditions. AMPK activation improves energy metabolism, stimulates autophagy, and inhibits inflammation, whereas HIF-1α increases angiogenesis and helps cells to adapt to severe conditions. First we will review how AMPK and HIF signaling mechanisms control the function of an integrated survival network which is able not only to improve the regulation of longevity but also support the progression of tumorigenesis. We will also describe distinct crossroads between the regulation of longevity and cancer, e.g. specific regulation through the AMPKα and HIF-α isoforms, the Warburg effect, mitochondrial dynamics, and cellular senescence.
Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. antero.salminen@uef.fi.
Antero
A
Salminen
Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.|Department of Ophthalmology, Kuopio University Hospital, P.O. Box 100, FI-70029, KYS, Finland.
Kai
K
Kaarniranta
Faculty of Health Sciences, School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
Anu
A
Kauppinen
D000091162:AMP-Activated Protein Kinase Kinases; D017677:Age Distribution; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008136:Longevity; D009369:Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D015995:Prevalence; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases
Ageing; Healthspan; Lifespan; Senescence; Tumorigenesis