Hypoxia Inducible Factor Activates the Transforming Growth Factor-α/Epidermal Growth Factor Receptor Growth Stimulatory Pathway in VHL-/- Renal Cell Carcinoma Cells

Gunaratnam, Lakshman; Morley, Melissa; Franovic, Aleksandra; Paulsen, Natalie De; Mekhail, Karim; Parolin, Doris A. E.; Nakamura, Eijiro; Lorimer, Ian A. J.; Lee, Stephen

doi:10.1074/jbc.m305502200

Cited by 182 publications

(153 citation statements)

References 66 publications

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“…Previous investigators have not reported suppression of EGFR protein after re-expression of wt-VHL (Knebelmann et al, 1998;Gunaratnam et al, 2003). However, in the report by Gunaratnam et al, (2003), adenovirus-mediated introduction of wt-VHL into 786-O cells visibly reduced EGFR levels (see their Figure 2A), although this difference was either discounted or not further clarified (Gunaratnam et al, 2003). In the report of Knebelmann et al, (1998), the Western blot appears too overexposed for optimal quantitation (Knebelmann et al, 1998).…”

Section: Discussionmentioning

confidence: 95%

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Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma

et al. 2005

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Epidermal growth factor receptor (EGFR) and tumour growth factor alpha (TGFa) are frequently overexpressed in renal cell carcinoma (RCC) yet responses to single-agent EGFR inhibitors are uncommon. Although von Hippel -Lindau (VHL) mutations are predominant, RCC also develops in individuals with tuberous sclerosis (TSC). Tuberous sclerosis mutations activate mammalian target of rapamycin (mTOR) and biochemically resemble VHL alterations. We found that RCC cell lines expressed EGFR mRNA in the near-absence of other ErbB family members. Combined EGFR and mTOR inhibition synergistically impaired growth in a VHLdependent manner. Iressa blocked ERK1/2 phosphorylation specifically in wt-VHL cells, whereas rapamycin inhibited phospho-RPS6 and 4E-BP1 irrespective of VHL. In contrast, phospho-AKT was resistant to these agents and MYC translation initiation (polysome binding) was similarly unaffected unless AKT was inhibited. Primary RCCs vs cell lines contained similar amounts of phospho-ERK1/2, much higher levels of ErbB-3, less phospho-AKT, and no evidence of phospho-RPS6, suggesting that mTOR activity was reduced. A subset of tumours and cell lines expressed elevated eIF4E in the absence of upstream activation. Despite similar amounts of EGFR mRNA, cell lines (vs tumours) overexpressed EGFR protein. In the paired cell lines, PRC3 and WT8, EGFR protein was elevated posttranscriptionally in the VHL mutant and EGF-stimulated phosphorylation was prolonged. We propose that combined EGFR and mTOR inhibitors may be useful in the subset of RCCs with wt-VHL. However, apparent differences between primary tumours and cell lines require further investigation.

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Section: Discussionmentioning

confidence: 95%

“…TGFa, an EGFR ligand under transcriptional control by HIF, is constitutively expressed in VHL mutant cells (Knebelmann et al, 1998;de Paulsen et al, 2001;Gunaratnam et al, 2003). These observations have led to clinical trials of EGFR inhibitors in RCC (Drucker et al, 2003;Motzer et al, 2003;Foon et al, 2004;Rowinsky et al, 2004;Amato, 2005).…”

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confidence: 99%

Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma

et al. 2005

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“…In that respect the majority of ccRCC, the most common subtype of renal cell cancer (RCC), bear biallelic-inactivating mutations of the VHL tumor suppressor gene [44]. As a consequence, VHL -/-ccRCC cells have a constitutive, oxygen-independent activation of HIF1α/HIF-2α [45]. Unregulated growth of these cells was reported to be promoted by activating the transforming growth factor-α (TGF-α)/EGFR pathway.…”

Section: Induction Of Rtk Ligandsmentioning

confidence: 99%

“…Unregulated growth of these cells was reported to be promoted by activating the transforming growth factor-α (TGF-α)/EGFR pathway. It was shown that overproduction of TGF-α by VHL -/-ccRCC is a direct consequence of HIF activation [45]. Notably, the use of EGFR inhibitors was as efficient as reintroducing VHL for abolishing the ability of ccRCC cells to form tumors in nude mice [46][47][48].…”

Section: Induction Of Rtk Ligandsmentioning

confidence: 99%

“…Expression induced by increased SRC activity [31] Rat pheochromocytoma cells, rat heart myocytes, rat glioma cells VEGF mRNA stabilization [32][33][34] MDA-MB-231 and MDA-MB-435 breast cancer cells, U87, U251 and A172 glioblastoma cells PDGF-B Transcriptional activation by HIF-1α [36,37] HEPG2 HCC cells, mouse IGF2 Increased expression indirectly mediated by HIF-embryonic fibroblast and embryonic stem cells 1α [41][42][43] 786-0 ccRCC cells TGFα Production induced by increased HIF in VHL null cells [45] Astrocytes isolated from stroke-prone spontaneously hypertensive rats…”

Section: Vegfmentioning

confidence: 99%

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Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

Glück

Aebersold

Zimmer

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Oxygen‐independent degradation of HIF‐α via bioengineered VHL tumour suppressor complex

et al. 2009

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Tumour hypoxia promotes the accumulation of the otherwise oxygen-labile hypoxia-inducible factor (HIF)-α subunit whose expression is associated with cancer progression, poor prognosis and resistance to conventional radiation and chemotherapy. The oxygen-dependent degradation of HIF-α is carried out by the von Hippel–Lindau (VHL) protein-containing E3 that directly binds and ubiquitylates HIF-α for subsequent proteasomal destruction. Thus, the cellular proteins involved in the VHL–HIF pathway have been recognized as attractive molecular targets for cancer therapy. However, the various compounds designed to inhibit HIF-α or HIF-downstream targets, although promising, have shown limited success in the clinic. In the present study, we describe the bioengineering of VHL protein that removes the oxygen constraint in the recognition of HIF-α while preserving its E3 enzymatic activity. Using speckle variance–optical coherence tomography (sv–OCT), we demonstrate the dramatic inhibition of angiogenesis and growth regression of human renal cell carcinoma xenografts upon adenovirus-mediated delivery of the bioengineered VHL protein in a dorsal skin-fold window chamber model. These findings introduce the concept and feasibility of ‘bio-tailored’ enzymes in the treatment of HIF-overexpressing tumours.

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Hypoxia Inducible Factor Activates the Transforming Growth Factor-α/Epidermal Growth Factor Receptor Growth Stimulatory Pathway in VHL-/- Renal Cell Carcinoma Cells

Abstract: These data link HIF with the overproduction of a bona fide renal cell mitogen leading to activation of a pathway involved in growth of renal cancer cells. Moreover, our results suggest that HIF might be involved in oncogenesis to a much higher extent than previously appreciated.

Cited by 182 publications

References 66 publications

Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma

Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma

Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

Oxygen‐independent degradation of HIF‐α via bioengineered VHL tumour suppressor complex

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