Differential effects of HIF-α isoforms on apoptosis in renal carcinoma cell lines

Cancer Cell International

Alan R Schoenfeld¹  Igor Lantsberg¹  Rajiv Pasricha¹  Donald Doukas¹  Michael D Gallo¹  Alana Doonachar¹ 

[1] Department of Biology, Adelphi University, One South Avenue, Garden City 11530-0701, NY, USA

关键词: VHL;    UV-irradiation;    Serum starvation;    HIF-alpha;    Glucose starvation;    Apoptosis;   

Others  :  1138472
DOI  :  10.1186/s12935-015-0175-3

 received in 2014-11-17, accepted in 2015-02-10,  发布年份 2015

【 摘 要 】

Background

Germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene predispose individuals to clear cell renal carcinomas, hemangioblastomas, and pheochromocytomas. The VHL gene product forms an ubiquitin E3 ligase complex, with regulation of hypoxia-inducible factor alpha (HIF-α) as its best known function. Lack of VHL expression has been shown previously to sensitize renal cells to apoptosis caused by certain cellular stresses. In this report, the role of HIF-α in apoptosis was investigated using two parent VHL-null renal carcinoma cell lines.

Methods

786-O and RCC10 renal carcinoma cell lines with manipulated levels of VHL, HIF-1α, or HIF-2α were subjected to cellular stresses and analyzed by western blotting for the abundance of apoptotic markers.

Results

Cell lines expressing mutant VHL proteins that were unable to regulate HIF-α had increased levels of apoptosis when irradiated with ultraviolet (UV) light. The influences of the two major isoforms of HIF-α, HIF-1α and HIF-2α, on apoptosis, were compared by creating cell lines in which levels of each isoform were modulated via short hairpin RNA interference. In UV-irradiated cells, HIF-2α expression was determined to promote apoptosis, whereas HIF-1α was anti-apoptotic. In cells deprived of either glucose or serum, HIF-1α expression was generally anti-apoptotic, while HIF-2α expression was observed to either promote apoptosis or have less of an influence on apoptosis, depending on the cell line used.

Conclusions

HIF-1α and HIF-2α exerted distinct effects in each of the conditions tested, with expression of HIF-1α largely blocking apoptosis and HIF-2α generally promoting apoptosis. These results reinforce that HIF-1α and HIF-2α have distinct biological roles and that their relative expression levels may influence some therapeutic interventions that are dependent on apoptosis.

【 授权许可】

   
2015 Doonachar et al.; licensee BioMed Central.

【 图 表 】

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