GADD45α sensitizes cervical cancer cells to radiotherapy via increasing cytoplasmic APE1 level.

Abstract

Radioresistance remains a major clinical challenge in cervical cancer therapy. However, the mechanism for the development of radioresistance in cervical cancer is unclear. Herein, we determined that growth arrest and DNA-damage-inducible protein 45α (GADD45α) is decreased in radioresistant cervical cancer compared to radiosensitive cancer both in vitro and in vivo. In addition, silencing GADD45α prevents cervical cancer cells from undergoing radiation-induced DNA damage, cell cycle arrest, and apoptosis. More importantly, our data show that the overexpression of GADD45α significantly enhances the radiosensitivity of radioresistant cervical cancer cells. These data show that GADD45α decreases the cytoplasmic distribution of APE1, thereby enhancing the radiosensitivity of cervical cancer cells. Furthermore, we show that GADD45α inhibits the production of nitric oxide (NO), a nuclear APE1 export stimulator, by suppressing both endothelial NO synthase (eNOS) and inducible NO synthase (iNOS) in cervical cancer cells. In conclusion, our findings suggest that decreased GADD45α expression significantly contributes to the development of radioresistance and that ectopic expression of GADD45α sensitizes cervical cancer cells to radiotherapy. GADD45α inhibits the NO-regulated cytoplasmic localization of APE1 through inhibiting eNOS and iNOS, thereby enhancing the radiosensitivity of cervical cancer cells.

• Authors: Qing Li, Xi Wei, Zhi-Wei Zhou, Shu-Nan Wang, Hua Jin, Kui-Jun Chen, Jia Luo, Kenneth D Westover, Jian-Min Wang, Dong Wang, Cheng-Xiong Xu, Jin-Lu Shan
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 5 Pg. 524 (05 01 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 29743554 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• GADD45A protein, human
• Neoplasm Proteins
• Nuclear Proteins
• APEX1 protein, human
• DNA-(Apurinic or Apyrimidinic Site) Lyase

Topics

• Animals
• Cell Cycle Proteins (metabolism)
• DNA-(Apurinic or Apyrimidinic Site) Lyase (metabolism)
• Female
• HeLa Cells
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Proteins (metabolism)
• Nuclear Proteins (metabolism)
• Radiation Tolerance
• Radiotherapy
• Uterine Cervical Neoplasms (metabolism, pathology, radiotherapy)