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Review
. 2015 Sep;5(5):378-89.
doi: 10.1016/j.apsb.2015.05.007. Epub 2015 Jun 6.

HIF-1α pathway: role, regulation and intervention for cancer therapy

Georgina N Masoud  1 , Wei Li  1
Affiliations
Review

HIF-1α pathway: role, regulation and intervention for cancer therapy

Georgina N Masoud et al. Acta Pharm Sin B. 2015 Sep.

Abstract

Hypoxia-inducible factor-1 (HIF-1) has been recognized as an important cancer drug target. Many recent studies have provided convincing evidences of strong correlation between elevated levels of HIF-1 and tumor metastasis, angiogenesis, poor patient prognosis as well as tumor resistance therapy. It was found that hypoxia (low O2 levels) is a common character in many types of solid tumors. As an adaptive response to hypoxic stress, hypoxic tumor cells activate several survival pathways to carry out their essential biological processes in different ways compared with normal cells. Recent advances in cancer biology at the cellular and molecular levels highlighted the HIF-1α pathway as a crucial survival pathway for which novel strategies of cancer therapy could be developed. However, targeting the HIF-1α pathway has been a challenging but promising progresses have been made in the past twenty years. This review summarizes the role and regulation of the HIF-1α in cancer, and recent therapeutic approaches targeting this important pathway.

Keywords: 4E-BP1, eukaryotic translation initiation factor 4E (eIF-4E) binding protein p70 S6 kinase (S6K); ADM, adrenomedullin; AKt, protein kinase B; ARD-1, arrest-defective-1; ARNT, aryl hydrocarbon nuclear translocator; AhR, aryl hydrocarbon receptor; C-MYC, myelocytomatosis virus oncogene cellular homolog; C-TAD, COOH-terminal TAD; CAC, circulating angiogenic cells; CPTs, camptothecins; Cancer drug discovery and development; ChIP, chromatin immunoprecipitation; CoCl2, cobalt chloride; DFO, deferoxamine; EGF, epidermal growth factor; ELISA, enzyme-linked immunosorbent assay; EMSA, electrophoretic mobility shift assay; EPO, erythropoietin; ERK, extracellular signal-regulated kinase; FIH-1, factor inhibiting HIF-1; GA, geldanamycin; GAs, geldanamycins; GLUT1, glucose transporter 1; GLUT3, glucose transporter 3; GLUTs, glucose transporters; HDAC, histone deacetylase; HIF-1α; HIF-1α inhibitors; HIF-1α, hypoxia-inducible factor-1α; HK1, hexokinase 1; HK2, hexokinase 2; HPH, HIF-1 prolyl hydroxylases; HRE, hypoxia response elements; HTS, high throughput screens; Hsp90, heat shock protein 90; ID2, DNA-binding protein inhibitor; IGF-BP2, IGF-factor-binding protein 2; IGF-BP3, IGF-factor-binding protein 3; IGF2, insulin-like growth factor 2; IPAS, inhibitory PAS; K, lysine residue; LDHA, lactate dehydrogenase; LEP, leptin; LRP1, LDL-receptor-related protein 1; Luc, luciferase; MAPK, mitogen-activated protein kinases; MEK, MAPK/ERK kinase; MNK, MAP kinase interacting kinase; MTs, microtubules; Mdm2, mouse double minute 2 homolog; N, asparagine residue; N-TAD, NH2-terminal TAD; NOS, nitric oxide synthase; ODDD, oxygen dependent degradation domain; P, proline residue; PAS, Per and Sim; PCAF, p300/CBP associated factor; PHDs, prolyl-4-hydroxylases; PI3K, phosphatidyl inositol-4,5-bisphosphate-3-kinase; PKM, pyruvate kinase M; RCC, renal cell carcinoma; RT-PCR, reverse transcription polymerase chain reaction; Raf, rapidly accelerated fibrosarcoma; Ras, rat sarcoma; SIRT 1, Sirtuin 1; TAD, transactivation domains; TGF-α, transforming growth factor α; TGF-β3, transforming growth factor beta3; TPT, topotecan; Top I, topoisomerase I; VEGF, vascular endothelial growth factor; bHLH, basic-helix-loop-helix; eIF-4E, eukaryotic translation initiation factor 4E; mTOR, mammalian target of rapamycin; pVHL, von Hippel-Lindau protein.

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Figures

None
Graphical abstract
Figure 1
Figure 1
Representative HIF-1α regulatory genes and their effects on cancer progression. LEP, leptin; NOS, nitric oxide synthase; VEGF, vascular endothelial growth factor; LRP1, LDL-receptor-related protein 1; ADM, adrenomedullin; TGF-β3, transforming growth factor-β3; EPO, erythropoietin; HK1, hexokinase 1; HK2, hexokinase 2; GLUT1, glucose transporter 1; GLUT3, glucose transporter 3; LDHA, lactate dehydrogenase; PKM, pyruvate kinase M; IGF2, insulin-like growth factor 2; IGF-BP2, IGF-factor-binding protein 2; IGF-BP3, IGF-factor-binding protein 3; TGF-α, transforming growth factor α; C-MYC, myelocytomatosis virus oncogene cellular homolog; ID2, DNA-binding protein inhibitor.
Figure 2
Figure 2
Functional domains (bHLH, PAS, TAD) for proteins related to bHLH-PAS family. HIF-1α and HIF-2α share high degree of amino acid sequence similarities and both of them have two distinct TADs (C-TAD and N-TAD). In contrast, HIF-3α only has N-TAD.
Figure 3
Figure 3
Regulation of HIF-1α pathway at different levels. (a) Growth factors related pathways; (b) pVHL related pathways; (c) FIH-1 pathway; (d) Mdm2-p53 mediated ubiquitination and proteasomal degradation pathway; (e) Hsp90. Ras/Raf/MEK: Rat sarcoma/rapidly accelerated fibrosarcoma/MAPK/ERK kinase. These pathways regulate HIF-1α activity by regulating HIF-1α synthesis (a), HIF-1α stability (b, d, e), or HIF-1α transactivation (e, c).
Figure 4
Figure 4
Schematic illustration of approaches adopted for discovery of HIF-1α inhibitors and investigation of their underlying inhibitory mechanisms of action (MOAs).
Figure 5
Figure 5
HIF-1α inhibitors modulate different levels of the HIF-1α activation pathway.
Figure 6
Figure 6
Chemical structures of molecules inhibiting HIF-1α pathway. Topotecan (3a): R1=OH, R2=CH2N(CH3)2, R3=H, R4=H; EZN-2208 (3b): R1=OH, R2=H, R3=CH2-CH3, R4=CO=CH2NHCOCH2O-(40k 4-arm-PEG); SN38 (3c): R1= OH, R2= H, R3= CH2CH3, R4=H; Everolimus (4a): R1=CH2CH2OH; Sirolimus (4b): R=OCH3; 2ME2 (8a): R1=OH, single bond, R2=OH; ENDM-1198 (8b): R1=CONH2, double bond, R2=H; ENMD-1200 (8c): R1=CONH2, single bond, R2==CH2; ENMD-1237 (8d): R1=CONH2, single bond, R2=H; GA (9a): R=OCH3; 17-AAG (9b): R=–CH2NHCH2CH=CH2; 17AG (9c): R=NH2; 17-DMAG (9d): R=–CH2NH(CH2)2N(CH3)2.
Figure 7
Figure 7
Chemical structures of molecules inhibiting HIF-1α pathway. Doxorubicin (18a): R=CH2OH; Danuorubicin (18b): R=CH3.
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