Hypoxia (HIF-1) as a major target of cancer therapy By, Prabhu Thirusangu, Molecular Biomedicine Laboratory, Sahyadri Science College, Kuvempu University, Shimoga, KA
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Hypoxia (HIF-1) as a major target of cancer therapy
By,Prabhu Thirusangu,Molecular Biomedicine Laboratory,Sahyadri Science College,Kuvempu University,Shimoga, KA
Tumor development
This course is funded with the support of the METOXIA project under the FP7 Programme.
Metastases
SpreadingInvasive growth
Therapy
Normal cell
Transformation
Cancer cell
Gene defectsSteps in carcinogenesis
Angiogenesis
Tumor
Hypoxia
Angiogenesis: growth of blood vessels
Uncontrolled cell growthAnti-apoptosis
Cell population
Apoptosis: programmed cell death
The response of Hypoxia to Oxygen
Structure of HIF-1
Dayan et al, Cancer Microenvironment (2008)
Structure of HIF-α & β
Dayan et al, Cancer Microenvironment (2008)
Garth Powis et al, Mol Cancer Ther 2004
Hypoxia signaling..
Importin α,β
Proteosomal degradation of HIF-1α
Luo et al, 2014 BioMed Research International
Proteosomal degradation of HIF-1α
Dayan et al, Cancer Microenvironment (2008)
Stabilization of HIF-1α
Soon-Sun Hong, et al, Cancer Research and Treatment 2004
Nuclear Accumulation of HIF-1α
PPhosphorilation by MAPK etc
P
Luo et al, 2014 BioMed Research International
HIF-1
hypoxia
Pol IIcomplexCBP/p300
HIF-1
HIF-1
Angiogenesis Glucosemetabolism
Cellproliferation
HIF-1 is a heterodimer
Wang et al
B
VHLC
Cul-2
HIFproteasome
PHD
HIF
HRE
VHL targets HIF for ubiquitination PHDs hydroxylate HIF
O2
O2
O2
O2
O2
HIF :activates genes involved in O2 homeostasis
Regulation of Hypoxia Inducible Genes
Holterman & Stephen Lee et al
O2
O2
O2
O2
O2
B
VHLC
Cul-2
HIF
proteasome
PHD
HIF
HRE
ub-HIF exported to cytoplasm for degradation
Regulation of Hypoxia Inducible Genes
Holterman & Stephen Lee et al
B
VHLC
Cul-2
proteasome
PHD
HIF
HRE
HIF
PHDs are inactivated in low oxygen tension HIF evades recognition by VHL and binds HIF
O2
O2
O2
O2
O2
Regulation of Hypoxia Inducible Genes
Holterman & Stephen Lee et al
HIF evades recognition by VHL and binds HIF
B
VHLC
Cul-2
proteasome
PHD
HIF HIF
Glut-1VEGFMMPTGF
HRE
HIF heterodimers activate hypoxia inducible genes
O2
Regulation of Hypoxia Inducible Genes
Holterman & Stephen Lee et al
Dayan et al, Cancer Microenvironment (2008)
From the ECM to HIF and from HIF to the ECM…
eIF-4E
Dayan et al, Cancer Microenvironment (2008)
From oxygen to HIF and from HIF to oxygen.
From nutrients to HIF and from HIF to metabolism
Dayan et al, Cancer Microenvironment (2008)
Soon-Sun Hong, et al, Cancer Research and Treatment 2004
Zimna et al, BioMed Research International 2014
HIF inhibitors could be tentatively divided in agents that modulate:
(1) HIF-1 mRNA expression,
(2) HIF-1 protein translation,
(3) HIF-1 protein degradation,
(4) HIF-1 nuclear translocation
(5) HIF-1 dimerization and DNA binding
(6) HIF-1 transcriptional activity.
Possible targets on Hypoxia signaling..
Points to be remembered….
A. What is HIF-1?
The studies of hypoxia response element of the erythropoietin gene leads to the discovery of HIF-1 by Semenza and Wang in 1992. Semenza GL & Wang GL. (1992). Mol. Cell. Biol. 12: 5447-5454.
HIF-1: Hypoxia Inducible Factor - 1
HIF-1 is a protein with DNA binding activity. It is composed of two subunits: HIF-1 and HIF-1.
Proline residue 402 & 564 in HIF-1 can be hydroxylated by prolyl hydroxylase.
The hydroxylation of proline causes the binding of von Hippel-Lindau tumor suppressor (VHL).
The binding of VHL leads to the ubiquitinylation of HIF-1.
Ubiquitinylation of HIF-1 results in degradation by proteasome. Bruick RK. (2002) Science. 295:807-808.
HIF-1 is constitutively made and degraded via VHL.
Prolyl hydroxylase is O2-dependent The activation of prolyl hydroxylase depends on
several co-factors such as O2, Fe2+, 2-OG, -ketoglutarate and ascorbate.
Under hypoxia, prolyl hydroxylase cannot be activated. Thus,
HIF-1 accumulates and translocates into nucleus. In the nucleus, it binds to HIF-1 forming HIF-1. HIF-1 binds to co-activators CBP/p300 and is then activated.
HIF-1 Target GenesErythropoeitin (EPO)Nitric oxide synthase 2 (NOS2)TransferrinTransferrin receptorVascular endothelial growth factor (VEGF)VEGF receptor FLT-1
Group 1: O2 Delivery
Aldolase AAldolase CEnolase 1 (ENO1) Glucose transporter 1Glyceraldehyde phosphate dehydrogenase Hexokinase 1Hexokinase 2Lactate dehydrogenase APhosphofructokinase LPhosphoglycerate kinase 1Pyruvate kinase M
Group 2: Glucose/Energy Metabolism
Insulin-like growth factor 2 (IGF-2)IGF binding protein 1IGF binding protein 3p21p35
Group 3: Cell Proliferation/Viability
Finally…Thank you.
Special Thanks to Dr. Wang for providing presentation skeleton
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