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IL-1ß-mediated up-regulation of HIF-1 via an NFB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis¹

YUN-JIN JUNG^*, JENNIFER S. ISAACS^*, SUNMIN LEE, JANE TREPEL and LEN NECKERS^*,2

^* Cell and Cancer Biology Branch, CCR, National Cancer Institute (NCI), Rockville, Maryland, USA; and
Medical Oncology Clinical Research Unit, CCR, NCI, Bethesda, Maryland, USA

² Correspondence: Cell and Cancer Biology Branch, CCR, NCI, 9610 Medical Center Dr., Suite 300, Rockville, MD 20850, USA. E-mail: len{at}helix.nih.gov

SPECIFIC AIM

There is growing evidence that inflammation is a contributing factor leading to cancer development, yet pathways involved in this progression are not well understood. While HIF-1, a heterodimeric transcription factor composed of inducibly expressed HIF-1 and constitutively expressed HIF-1ß, regulates genes that play essential roles in tumor progression and HIF-1 activity is up-regulated in inflammatory conditions, there is no prior evidence suggesting a role for HIF-1 as a link between inflammation and the development of cancer. Therefore, we investigated whether the HIF-1 signaling pathway was stimulated by the proinflammatory cytokine interleukin-1 ß (IL-1ß) -induced inflammatory signal in A549 cells.

PRINCIPAL FINDINGS

1. HIF-1 induction by IL-1ß is mediated by NFB
To test whether IL-1ß was able to induce HIF-1 protein, we treated the lung epithelial cell line A549 with IL-1ß under normoxia. HIF-1 protein was markedly induced by IL-1ß. Because the proinflammatory cytokine IL-1ß activates nuclear factor-B (NFB) as a major inflammatory signal, we examined whether the IL-1-mediated induction of HIF-1 occurred through an NFB-dependent pathway. IL-1ß treatment elicited at least a fivefold induction of NFB activity as measured using an NFB-dependent luciferase reporter; molecular and pharmacological inhibitors of NFB dramatically reduced NFB activity induced by Il-1ß. All NFB inhibitors tested significantly attenuated the ability of IL-1ß to up-regulate HIF-1 protein level. Although HIF-1 induction by IL-1ß requires NFB-mediated transcription, RT-PCR analysis revealed that HIF-1 mRNA levels remained unchanged in response to IL-1ß.

2. The PI-3 kinase–AKT–mTOR pathway is an upstream signaling pathway for IL-1-mediated NFB activation and HIF-1 up-regulation
IL-1 activates NFB through the PI-3 kinase–AKT pathway in many cell types and PI-3 kinase–AKT–mTOR is a signaling pathway leading to induction of HIF-1 in normoxia. We examined whether the PI-3 kinase pathway is involved in IL-1-mediated NFB activation and subsequent HIF-1 induction. Treatment with IL-1ß induced serine 473 phosphorylation of AKT, the active form of AKT, in a PI-3 kinase-dependent manner. Treatment with LY-294002, a specific inhibitor of PI-3 kinase, or rapamycin, a specific inhibitor of mTOR kinase (a downstream target of PI-3K/AKT), attenuated NFB activity mediated by IL-1ß, indicating that PI-3K-AKT-mTOR is an upstream signaling pathway for IL-1-mediated NFB activation in this cell line. HIF-1 protein levels were significantly decreased in the presence of either LY294002 or rapamycin. Therefore, HIF-1 protein levels correlate with NFB activity and are dependent on activation of the AKT pathway in response to IL-1ß.

3. NFB-induced COX-2 mediates HIF-1 up-regulation by IL-1ß
Since IL-1ß does not increase HIF-1 protein by modulating its transcription, this strongly suggests that genes induced by NFB-dependent transcription are critical for HIF-1 up-regulation. A strong candidate gene for NFB-mediated HIF-1 up-regulation is COX-2, an NFB-inducible gene that plays important roles in inflammation and carcinogenesis and is implicated in modulating VEGF expression, a target gene of HIF-1. IL-1ß was able to induce COX-2 and the induction was inhibited by NFB inhibitors, indicating that IL-1-mediated COX-2 induction is NFB dependent (Fig. 1 A). To examine whether NFB-induced COX-2 was involved in HIF-1 induction by IL-1ß, cells were treated with IL-1ß in the presence of COX-2 inhibitors. HIF-1 induction was inhibited by the COX-2 inhibitors (Fig. 1B , upper panel). In contrast, a specific COX-1 inhibitor was unable to interfere with the ability of IL-1ß to induce HIF-1 protein (Fig. 1B , lower panel), thus confirming the specificity for COX-2. Since COX-2 plays an important role in the initiation and progression of colon cancer, we examined whether COX-2 is involved in the regulation of HIF-1 protein levels in a colon epithelial cell line, CaCo-2. As in A549 cells, COX-2 was induced in response to IL-1ß in a NFB-dependent manner (Fig. 1C , upper panel) and inhibition of COX-2 correlated with a dose-dependent attenuation of IL-1-induced HIF-1 protein (Fig. 1C , lower panel). Further, PGE₂ a biologically active product of COX-2, induced HIF-1 protein in a dose-dependent manner (Fig. 1D ).

View larger version (24K): [in this window] [in a new window]   Figure 1. NFB-dependent COX-2 induction mediates HIF-1 up-regulation. A) A549 cells were transfected with NFB super repressor plasmid or pretreated with D609 followed by treatment with IL-1ß for 4 h. Cells were lysed and COX-2 levels were detected in the cytosolic extract. B) A 549 cells were treated with IL-1ß in the presence of the general COX-2 inhibitor indomethacin (25 µM), the specific COX-2 inhibitor NS-398, or the COX-1-specific inhibitor SC-560 (1 µM) and HIF-1 levels were monitored from nuclear extracts. C) Upper panel: CaCo-2 cells were treated with IL-1ß for 4 h in the presence of the NFB inhibitors pyrrolidine dithiocarbamate (50 µM, PDTC) or BAY 11-7082 (BAY, 20 µM) and COX-2 protein was detected from cytosolic extracts. Lower panel: CaCo-2 cells were treated with IL-1ß in the presence of NS-398 and HIF-1 protein was detected from nuclear extracts. D) A549 cells were treated with prostaglandin E2 (PGE2) for 1 h and the HIF-1 level was detected from nuclear extracts.

4. Induction of HIF-1 by IL-1ß is dependent on VHL function
We examined whether IL-1ß was capable of stabilizing HIF-1 protein by comparing the stability of HIF-1 in IL-1-treated cells to that in untreated cells. While endogenous HIF-1 protein was extremely labile, with a <4 min half-life, IL-1ß treatment stabilized HIF-1 protein and extended its half-life threefold. One of the main regulators of HIF-1 protein degradation is the ubiquitin protein ligase VHL. Therefore, we investigated the possible involvement of VHL in IL-1-mediated HIF-1 stabilization. In an experiment using a matched pair of renal carcinoma cells lines either lacking VHL function (UMRC2) or with VHL replaced (UMRC2/VHL), we observed that HIF-1 protein was induced in VHL-restored UMRC2 cells in response to IL-1ß, but not in VHL-lacking UMRC. To further confirm this, we transfected A549 cells with HA-tagged wild-type HIF-1 plasmid (VHL-sensitive) or HA-tagged proline mutated HIF-1 (VHL-resistant). Consistent with our other results, only wild-type HIF-1, not proline mutated HIF-1, was induced in response to IL-1ß.

5. IL-1-mediated HIF-1 up-regulation stimulates VEGF production
Since vascular endothelial growth factor (VEGF) is an HIF-1 target gene through which HIF-1 plays a critical role in tumor progression, we examined whether HIF-1 up-regulated via the IL-1/NFB/COX-2 pathway could lead to an elevation in VEGF levels. IL-1ß induced VEGF mRNA threefold, and this effect was completely inhibited by an HIF-1-specific inhibitor (Fig. 2 A). To confirm this result, we examined accumulation of immunoreactive VEGF in cell culture supernatants. Consistent with the data in Fig. 2A , whereas IL-1ß enhanced VEGF secretion, the HIF-1 inhibitor prevented this increase, with VEGF levels returning to control values(Fig. 2B ). COX-2 inhibitors inhibited the IL-1ß-stimulated accumulation of VEGF by >50% (Fig. 2C ), consistent with our data demonstrating inhibition of the IL-1ß stimulatory effect on HIF-1 by these same agents (Fig. 1B , upper panel).

View larger version (13K): [in this window] [in a new window]   Figure 2. IL-1ß induces vascular endothelial growth factor (VEGF) in an HIF-1-dependent manner. A) A549 cells were treated with IL-1ß (500 pg/mL) in the presence or absence of the HIF-1-specific inhibitor NSC-609699 (1 µM) and RT-PCR was performed from total RNA. B) A549 cells were treated as in panel A, and immunoreactive VEGF protein in the cell culture supernatants was measured using the Quantikine VEGF ELISA kit. Data represent the mean of 3 separate experiments. C) A 549 cells were treated with IL-1ß for 8 h in the presence of NS-398 (25 µM) or indomethacin (25 µM) and VEGF protein levels were measured as in panel B. Data represent the mean of 3 separate experiments.

CONCLUSIONS

In this study, HIF-1 is identified as a molecular link between the inflammatory and oncogenetic pathways. IL-1-mediated HIF-1 induction is dependent on NFB transcriptional activity and this activity is correlated with HIF-1 protein levels.

Our data strongly suggest that the PI-3K–AKT–mTOR pathway is an upstream regulator of IL-1-mediated-NFB activation and subsequent HIF-1 induction. This is supported by the following data: 1) IL-1ß induces 473 serine phosphorylation of AKT in a PI-3 kinase-dependent manner, 2) specific inhibition of PI-3 kinase or mTOR (a downstream target of AKT) abrogates IL-1-mediated NFB-dependent luciferase expression, and 3) inhibition of AKT or mTOR prevents IL-1-mediated HIF-1 induction. These results are consistent with other reports showing an involvement of the PI-3K–AKT pathway in NFB activation and with data demonstrating that PI-3 kinase inhibition antagonizes HIF-1 induction by IL-1ß. Furthermore, HIF-1 has been reported to be regulated by an mTOR-dependent pathway.

We demonstrate COX-2-mediated HIF-1 induction in a lung epithelial cell line and a colon cell line. Our data demonstrate that IL-1-mediated activation of NFB increases COX-2 protein. We identified COX-2 as a potent effector for HIF-1 up-regulation and validated this observation by showing attenuation of IL-1-mediated HIF-1 up-regulation by COX-2 inhibitors. Prostaglandin E₂ (PGE₂), a major physiological product of COX-2, is also able to induce HIF-1 protein.

While some stimuli can promote HIF-1 protein up-regulation as a result of increased translation, our data showing increased stability of HIF-1 protein in IL-1ß-treated cells, and VHL dependency of IL-1-mediated HIF-1 up-regulation suggest that IL-1ß up-regulates HIF-1 by inhibiting its VHL-dependent degradation.

Finally, we provide evidence that IL-1-mediated VEGF induction is HIF-1 dependent and proceeds via a pathway involving NFB activation and COX-2 expression. Consistent with our observations, nonsteroidal anti-inflammatory drugs have recently been shown to possess anti-tumorigenic properties and can potently down-regulate COX-2-mediated VEGF expression. Recent in vivo studies demonstrating that host-derived IL-1ß is critical for tumor growth, angiogenesis and invasiveness should be revisited in light of the IL-1–HIF-1–VEGF connection.

View larger version (20K): [in this window] [in a new window]   Figure 3. Intracellular signaling mechanism for IL-1-mediated HIF-1 up-regulation. A proinflammatory signal (IL-1-NFB-COX-2) is translated into an oncogenic signal (VEGF stimulation) through HIF-1 up-regulation and VEGF secretion. IB-p represents phosphorylated inhibitory B protein. The dashed arrow suggests NFB-mediated transcription of additional cellular modulators that contribute to HIF-1 activation.

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-0329fje; doi: 10.1096/fj.03-0329fje

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