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.