Abstract
Constitutive expression of hypoxia-inducible factor (HIF) has been implicated in several proliferative disorders. Constitutive expression of HIF1 alpha and HIF2 alpha has been linked to a number of human cancers, especially renal cell carcinoma (RCC), in which HIF2 alpha expression is the more important contributor. Expression of HIF1 alpha is dependent on the mammalian target of rapamycin (mTOR) and is sensitive to rapamycin. In contrast, there have been no reports linking HIF2 alpha expression with mTOR. mTOR exists in two complexes, mTORC1 and mTORC2, which are differentially sensitive to rapamycin. We report here that although there are clear differences in the sensitivity of HIF1 alpha and HIF2 alpha to rapamycin, both HIF1 alpha and HIF2 alpha expression is dependent on mTOR. HIF1 alpha expression was dependent on both Raptor (a constituent of mTORC1) and Rictor (a constitutive of mTORC2). In contrast, HIF2 alpha was dependent only on the mTORC2 constituent Rictor. These data indicate that although HIF1 alpha is dependent on both mTORC1 and mTORC2, HIF2 alpha is dependent only on mTORC2. We also examined the dependence of HIF alpha expression on the mTORC2 substrate Akt, which exists as three different isoforms, Akt1, Akt2, and Akt3. Interestingly, the expression of HIF2 alpha was dependent on Akt2, whereas that of HIF1 alpha was dependent on Akt3. Because HIF2 alpha is apparently more critical in RCC, this study underscores the importance of targeting mTORC2 and perhaps Akt2 signaling in RCC and other proliferative disorders in which HIF2 alpha has been implicated.
Highlights
Hypoxia-inducible factor (HIF)2 is a critical transcriptional regulator of cellular responses to a variety of stressful conditions [1, 2]
We recently reported that elevated expression of both HIF1␣ and HIF2␣ in von Hippel-Lindau (VHL)-deficient renal cell carcinoma (RCC) cell lines is dependent on phospholipase D (PLD) [17]
Because PLD activity has been widely implicated in the activation of mammalian target of rapamycin (mTOR) [32], we investigated the effect of rapamycin on the expression of HIF2␣ in VHL-null 786-O RCC cells, which have elevated expression of HIF2␣, and in VHL-null RCC4 cells, which express both HIF1␣ and HIF2␣
Summary
Differential Dependence of Hypoxia-inducible Factors 1␣ and 2␣ on mTORC1 and mTORC2*. We report here that there are clear differences in the sensitivity of HIF1␣ and HIF2␣ to rapamycin, both HIF1␣ and HIF2␣ expression is dependent on mTOR. There have been several reports that HIF1␣ is sensitive to rapamycin [13,14,15,16], indicating that HIF1␣ expression is dependent upon mTORC1. We recently reported that elevated expression of both HIF1␣ and HIF2␣ in VHL-deficient RCC cell lines is dependent on phospholipase D (PLD) [17]. Like HIF␣, PLD has been implicated in stress responses [18] and has been shown to provide a survival signal in several human cancer cell lines [17,18,19,20,21]. Because HIF2␣ expression is critical for RCC tumorigenesis, this study indicates that targeting mTORC2 signals represents a viable therapeutic strategy in RCC and perhaps other cancers in which HIF2␣ is critical for tumorigenesis
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