# Differential Effects of the Prolyl-Hydroxylase Inhibitor on the Cellular Response to Radiation

## TL;DR

A drug used for kidney anemia changes how cancer cells respond to radiation, with effects varying by cell type and possibly involving a protein called DEC2.

## Contribution

The study reveals cell-specific effects of a prolyl-hydroxylase inhibitor on radiation sensitivity, possibly mediated by DEC2 and p53 signaling.

## Key findings

- PHI treatment increased radiation resistance in PC9 and HSC2 cells but sensitized A549 and TIG3 cells.
- DEC2 knock-down sensitized A549 and PC9 cells to radiation under PHI treatment.
- p53 silencing desensitized A549 but not PC9 cells to radiation, regardless of PHI treatment.

## Abstract

The prolyl-hydroxylase inhibitor (PHI), used effectively in several countries for the treatment of renal anemia, activates the multifunctional hypoxia-inducible factors (HIFs). While hypoxic conditions in tumors are known to affect the response to radiation therapy, the effect of PHI on the radiation response of cancer cells has not been determined. Hypoxic pretreatment increased the radiation sensitivity of A549 lung adenocarcinoma cells, whereas hypoxic culture after irradiation decreased the radiation sensitivity of HSC2 oral squamous cell carcinoma cells. Treatment of PC9 lung adenocarcinoma and HSC2 cells with the PHI FG-4592 significantly increased radiation resistance, whereas A549 and TIG3 lung fibroblast cells tended to be sensitized, suggesting cell type-specific differential effects of PHI. Quantitative RT-PCR analyses revealed that the basal and radiation-inducible expressions of DEC2, BAX, and BCL2 may be related to PHI-mediated radiation responses. Knock-down experiments showed that silencing of DEC2 sensitized both A549 and PC9 cells under PHI-treated conditions. On the other hand, silencing of p53, which regulates BAX/BCL2, desensitized A549 cells expressing wild-type p53, but not PC9 cells, with mutant-type p53, to irradiation, regardless of whether PHI was treated or not. Taken together, PHI modifies radiation responses in a cell type-specific manner, possibly through DEC2 signaling.