The Biphasic Role of the Hypoxia-Inducible Factor Prolyl-4-Hydroxylase, PHD2, in Modulating Tumor-Forming Potential

Abstract

Hypoxia is a common feature of solid tumors. The cellular response to hypoxic stress is controlled by a family of prolyl hydroxylases (PHD) and the transcription factor hypoxia-inducible factor 1 (HIF1). To investigate the relationship between PHD and HIF1 activity and cellular transformation, we characterized the expression levels of PHD isoforms across a lineage of cell strains with varying transformed characteristics. We found that PHD2 is the primary functional isoform in these cells and its levels are inversely correlated to tumor-forming potential. When PHD2 levels were altered with RNA interference in nontumorigenic fibroblasts, we found that small decreases can lead to malignant transformation, whereas severe decreases do not. Consistent with these results, direct inhibition of PHD2 was also shown to influence tumor-forming potential. Furthermore, we found that overexpression of PHD2 in malignant fibroblasts leads to loss of the tumorigenic phenotype. These changes correlated with HIF1A activity, glycolytic rates, vascular endothelial growth factor expression, and the ability to grow under hypoxic stress. These findings support a biphasic model for the relationship between PHD2 activity and malignant transformation. (Mol Cancer Res 2008;6(5):829 -42)

Knockdown of prolyl‐4‐hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA‐MB‐231 cells by affecting TGF‐β1 processing

“…18 In MDA-MB-231 cells, we found a significantly delayed and impaired tumor growth as a result of downregulating PHD2 by stable transfection of an shRNAencoding, plasmid-targeting PHD2. This tumor inhibiting Cancer Cell Biology effect could be associated with an altered processing of TGFb1.…”

“…Moreover PHD2 expression levels seem to critically affect tumor growth. 18 In this regard, it is important to mention that a reestablished tumor growth was observed for the reconstituted #4 MDA-MB-231 knockdown cells. Tumor growth, however, was still decreased compared to the wt cells.…”

“…17 In addition, a biphasic model for the relationship between PHD2 and tumor-forming potential has been suggested: small decreases of PHD2 lead to malignant transformation of nontumorigenic fibroblasts, whereas strongly decreased PHD2 levels do not. 18 Several PHD2 dependently regulated molecules have been identified, which mediate the tumor-inducing effects in stably transfected PHD2 knockdown tumor models like IL-8, angiogenin and amphiregulin 12,13 ; however, there is less knowledge about the molecular events, which are associated with the tumor-inhibiting effects of PHD2.…”

Mechanisms of Resistance to Anti-Angiogenic Therapy and Development of Third-Generation Anti-Angiogenic Drug Candidates

“…However, the role of PHD2 in tumor biology is complex, as this oxygen sensor might regulate different oncogenic versus tumor-suppressive mechanisms in a dose-dependent manner. 139 The role of PHD2 in human cancer is largely unknown, but one study documented a correlation of intratumoral PHD2 levels with a more aggressive phenotype of human head-and-neck cancer, which might provide a rationale to generally inhibit tumoral PHD2. 140 In any case, further study is required to develop specific PHD2 inhibitors for clinical use in the future.…”

Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis

“…Overexpression of all three PHDs and the asparaginyl hydroxylase factor inhibiting HIF correlated with tumor aggressiveness and higher rate of recurrence in pancreatic endocrine tumors (Couvelard et al, 2008). In addition, a biphasic model for the relationship between PHD2 and tumor-forming potential has been suggested: small decreases of PHD2 led to malignant transformation of non-tumorigenic fibroblasts, whereas strongly decreased PHD2 levels did not (Lee et al, 2008). In summary, the function of PHDs in cancer remains incompletely understood.…”