Effects of hypoxia and HIFs on cancer metabolism

Abstract

Cancer cells are characterized by rapid proliferation and require adaptive metabolic responses to allow continued biosynthesis and cell growth in the setting of decreased oxygen (O 2 ) and nutrient availability. The hypoxia-inducible factors (HIFs) are a common link between adaptation to low O 2 , changes in cancer metabolism, and malignant progression. The HIF-a subunits differentially regulate metabolic enzymes and other key factors involved in glycolysis, changes in redox status, and oxidative phosphorylation. Importantly, metabolic changes can, in turn, regulate HIF activity. Finally, changes in metabolism under hypoxia lead to important crosstalk between cancer cells and the stromal compartment of the microenvironment.Keywords Hypoxia Á HIF Á Cancer metabolism Á Tumor microenvironment Hypoxia-inducible factors and their regulationA majority of healthy tissues experience 2-9 % O 2 , while hypoxia is defined as less than 2 % O 2 [1]. Low O 2 tensions are often exhibited by regions of intense inflammation such as within arthritic joints, regions of the bone marrow, and in highly proliferative cancer cells [2]. Hypoxia may occur secondary to necrosis or aberrant neovascularization resulting in poor perfusion. Additionally, cancer cells may also proliferate rapidly enough to outstrip their blood supply [3]. Cells adapt to changes in O 2 availability by altering gene expression of crucial metabolic enzymes in order to counter changes in nutrient availability and redox status. This response is mediated, in part, by O 2 -labile transcription factors hypoxia-inducible factors HIF-1a and HIF-2a, key regulators of cellular adaptation to hypoxic stress [3][4][5].Comprised of an O 2 -sensitive a subunit and constitutively expressed b subunit, HIFs are primarily regulated through post-translational modification and stabilization and are part of the basic helix-loop-helix-PAS (bHLH/ PAS) family of transcription factors [6]. Under normal O 2 tensions, prolyl hydroxylase domain enzymes (PHDs) hydroxylate two conserved proline residues (405 and 531 in HIF-1a) within the O 2 -dependent degradation (ODD) domain of the HIF-a subunit. After hydroxylation, the von Hippel-Lindau (VHL) tumor suppressor E3 ligase complex polyubiquitinates HIF-a and targets it for eventual degradation by the 26S proteasome [7][8][9]. Under low O 2 , HIFs are no longer modified by PHDs, but instead dimerize with ARNT/HIF-1b through HLH and PAS domain interactions, translocate to the nucleus, and recruit coactivators such as CBP/p300. HIF heterodimers bind and recognize hypoxiaresponse elements (HREs), with the consensus sequence G/ACGTG, within the promoter regions of target genes and drive adaptive gene transcription [10][11][12][13] (Fig. 1). While the HIF-1a subunit is expressed ubiquitously, HIF-2a is selectively expressed in a much more tissue-restricted manner but can be found at high levels in vascular endothelial cells and myeloid-derived cells [14].V. Mucaj and J.E.S. Shay contributed equally to this work.

Stress-induced cleavage of Myc promotes cancer cell survival

“…Hypoxia and nutrient deprivation lead to cytoplasmic accumulation of Myc and conversion into Myc-nick Different areas within tumors are known to be exposed to variable levels of nutrients and oxygen, depending on their proximity to blood vessels and stroma (Mucaj et al 2012). Therefore, we considered that the variability in the presence of Myc forms could be caused by local heterogeneity in the microenvironment, leading to increased conversion of Myc into Myc-nick.…”

Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells: impact on response to chemotherapy

“…[1][2][3][4][5][6] Leukemic cells can infiltrate the niches leading to their enhanced self-renewal and proliferation, quiescence and resistance to chemotherapeutic agents. 7,8 Hypoxia is, therefore, associated with poor prognosis in leukemia, especially in acute myeloid leukemia (AML), [9][10][11][12][13] as also described in cancer and inflammatory diseases. 8,14 Adaptation of leukemic cells to the bone marrow microenvironment is important in the clonal selection that leads to leukemia progression, drug resistance and relapse.…”

“…7,8 Hypoxia is, therefore, associated with poor prognosis in leukemia, especially in acute myeloid leukemia (AML), [9][10][11][12][13] as also described in cancer and inflammatory diseases. 8,14 Adaptation of leukemic cells to the bone marrow microenvironment is important in the clonal selection that leads to leukemia progression, drug resistance and relapse. [7][8][9][10][11]14 To survive in hypoxia, cells activate adaptive responses, including gene regulation by hypoxia-inducible factors (HIF)-1alpha (HIF-1α) and -2alpha (HIF-2α).…”

“…8,14 Adaptation of leukemic cells to the bone marrow microenvironment is important in the clonal selection that leads to leukemia progression, drug resistance and relapse. [7][8][9][10][11]14 To survive in hypoxia, cells activate adaptive responses, including gene regulation by hypoxia-inducible factors (HIF)-1alpha (HIF-1α) and -2alpha (HIF-2α). 15,16 Hypoxia allows HIF to escape from normoxia-mediated degradation in the cytoplasm and to translocate into nuclei where they bind to hypoxia-response elements within the regulatory regions of target genes [17][18][19][20] and microRNA.…”

A new twist in neuroendocrine tumor research: Pacak-Zhuang syndrome, HIF-2α as the major player in its pathogenesis and future therapeutic options

“…This allows crosstalk between different signaling pathways resulting in cell transformation and tumor development 25,45,46 . Deregulation of HIFα has long been implicated in tumorigenesis since there is an interaction of HIF with many pivotal signaling pathways and (pseudo)hypoxia is found in almost all cancers 25,34,[46][47][48][49] . Both HIF-1α and HIF-2α seem to act as master regulators in adaptation of cancer progenitor/stem cells and their differentiated progenies to oxygen and nutrient deprivation (for a review, see Mimeault et al 50 ).…”