ReviewRegulation of cancer cell metabolism by hypoxia-inducible factor 1
Introduction
For decades, students of biochemistry have learned that in the presence of O2 cells generate ATP by completely oxidizing glucose to carbon dioxide and water through the activity of glycolytic enzymes, pyruvate dehydrogenase (PDH), the tricarboxylic acid (TCA) cycle enzymes, and the electron transport chain. In contrast, under hypoxic conditions, glucose is converted to lactate, through the activity of glycolytic enzymes and lactate dehydrogenase A (LDHA), which is a much less efficient means of generating ATP. Lactate production has been viewed as a default pathway that is followed when O2 is not available for respiration. However, lactate production increases several-fold when cells are exposed to 1% O2 (corresponding to a partial pressure [PO2] of ∼7 mmHg at sea level), which is well above the critical O2 concentration required for electron transport chain activity in isolated mitochondria (∼0.1 μM; PO2 = 0.05 mmHg). Recent studies have demonstrated that the switch from oxidative to glycolytic metabolism is an active response to hypoxia that is mediated by hypoxia-inducible factor 1 (HIF-1).
Section snippets
HIF-1
HIF-1 is a heterodimeric protein, composed of HIF-1α and HIF-1β subunits [1], [2], which modulates the regulation of hundreds of genes according to the cellular O2 concentration [3]. HIF-1α levels increase dramatically as O2 concentration declines [4]. Under normoxic conditions, HIF-1α is subjected to ubiquitination and proteasomal degradation [5], [6], [7] due to the binding of the von Hippel-Lindau tumor suppressor protein [8], which is the substrate recognition subunit of an E3
Intratumoral PO2, lactate, and pH
The mean PO2 in human tumors is significantly reduced compared to surrounding normal tissue and tumors with the greatest reduction in PO2 are most likely to invade, metastasize, and kill the patient [15]. Many carcinomas also manifest an increased concentration of lactate, which is also associated with increased risk of metastasis [16]. The increased lactate production is associated with increased expression of LDH-A [17] and the monocarboxylate transporter MCT4, which transports lactate out of
Effects of HIF-1α deficiency on cell metabolism
When HIF-1α-null mouse embryo fibroblasts (MEFs) are subjected to hypoxia for 3 days, the cells die due to increased production of reactive oxygen species (ROS) [22], [23]. In contrast, ROS levels decrease in wild type (WT) cells in response to chronic hypoxia. This adaptive response is mediated by HIF-1 through the transactivation of genes encoding pyruvate dehydrogenase kinase 1 (PDK1) and BNIP3. In hypoxic cells, PDK1 phosphorylates and inactivates PDH, thereby blocking the conversion of
The molecular basis of the Warburg effect in renal clear-cell carcinoma
Although many cancer cells utilize the physiological responses to hypoxia described above, in some cancers, genetic alterations can result in a fixed and O2-independent reprogramming of metabolism. Warburg noted increased production of lactate in the tissue culture media of liver tumor explants as compared to normal liver explants cultured under aerobic conditions [28]. In renal cell carcinoma lines in which VHL is inactivated by mutation, HIF-1α and HIF-2α are constitutively expressed and
Increased ROS levels and HIF-1α-dependent growth of tumor xenografts
The induction of HIF-1 activity by ROS appears to play an important role in cancer biology. Treatment of mice bearing tumor xenografts with N-acetyl cysteine or ascorbic acid results in a marked inhibition of tumor growth that is dependent upon the ability of these antioxidants to induce degradation of HIF-1α via the PHD2-VHL pathway [31]. Forced expression in cancer cells of a mutant form of HIF-1α that is resistant to PHD2-VHL-dependent degradation renders the cells resistant to the
Therapeutic implications
Clinical studies are warranted to determine whether inhibition of HIF-1 by antioxidants may improve outcome in patients with cancers in which HIF-1α overexpression is associated with poor prognosis (Table 1). However, this approach would not be efficacious in renal clear-cell carcinoma in which PHD2 activity is irrelevant due to VHL loss-of-function. Fortunately, other HIF-1 inhibitors have a mechanism of action that is independent of the PHD2-VHL pathway. For example, HSP90 inhibitors, such as
Conflict of interest
None declared.
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