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J. Biol. Chem., Vol. 280, Issue 34, 30120-30128, August 26, 2005

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Loss of the von Hippel Lindau Tumor Suppressor Disrupts Iron Homeostasis in Renal Carcinoma Cells^*

Alessandra Alberghini, Stefania Recalcati, Lorenza Tacchini, Paolo Santambrogio¶, Alessandro Campanella¶, and Gaetano Cairo||

From the Institute of General Pathology, University of Milan, Via Mangiagalli 31, 20133 Milan and the ^¶Protein Engineering Unit, Dibit, Scientific Institute of Recovery and Care, Saint Raffaele Hospital, Via Olgettina 58, 20132 Milan, Italy, and Internal Medicine 3, Ospedale Maggiore Policlinico, Milano, Italy

Given the modulation of iron metabolism by hypoxia and the high iron requirement of neoplastic cells, we investigated iron metabolism in a human renal cancer cell line with a mutated von Hippel Lindau (VHL) tumor suppressor gene (RCC10) and in a transfectant clone with wild-type VHL (RCC63). The loss of VHL strongly up-regulated transferrin receptor expression in RCC10 cells as a result of hypoxia inducible factor-1 (HIF-1)-mediated transcriptional activation, leading to an increased uptake of transferrin-bound ⁵⁵Fe. Increased iron availability did not compromise the resistance of VHL-defective cells to oxidative stress or promote faster cell multiplication. Surprisingly, the content of ferritin H and L subunits and ferritin mRNA levels were considerably lower in the RCC10 than in the RCC63 cells. Despite the similarities between HIF-1 and iron regulatory protein 2 (IRP2), we found no evidence of specific regulation of IRP2 by VHL. However, both IRP2 and IRP1 were slightly activated in RCC10 cells, thus indicating that this cell line has a somewhat reduced labile iron pool (LIP). The finding that RCC10 cells had a lower ferritin content but more ferritin-associated ⁵⁵Fe than RCC63 explains why VHL-lacking cells may have a smaller LIP despite increased iron uptake. We also found a correlation between cytoprotection from iron-mediated damage and efficient incorporation into ferritin of both transferrin and non-transferrin-bound ⁵⁵Fe. This study shows that, like oncogene activation, the loss of an oncosuppressor rearranges the expression pattern of the genes of iron metabolism to increase iron availability. However, in the case of VHL loss, mechanisms affecting iron handling by ferritin somehow counteract the effects that the reduced content of this protective protein may have on proliferation and oxidant sensitivity.

Received for publication, January 26, 2005 , and in revised form, June 27, 2005.

^* This work was supported by grants from the Italian Association for Cancer Research, Ministero dell'Istruzione, dell'Università e della Ricerca (Fondo per gli Investimenti della Ricerca di Base and Cofinanziamento 2001 and 2002) (to G. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed. Tel.: 39-025-031-5350; Fax: 39-025-031-5338; E-mail: gaetano.cairo{at}unimi.it.

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