Calreticulin Expression Controls Cellular Redox, Stemness, and Radiosensitivity to Function as a Novel Adjuvant for Radiotherapy in Neuroblastoma

Author:

Chen Chih-Jung123,Hu Ya-Chuan4,Chien Yueh56,Huang Wei-Chieh78,Wu Chi-Sheng910,Tsai Chung-Ying11,Lin Yang-Hsiang12,Lee Meng-Shiue56,Chien Chian-Shiu56ORCID,Yang Yi-Ping56,Lee Meng-Chou131415,Tseng Chung-Chih1617ORCID,Chi Hsiang-Cheng78ORCID

Affiliation:

1. Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan

2. School of Medicine, Chung Shan Medical University, Taichung, Taiwan

3. Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan

4. Nutrition Room of Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung City, Taiwan

5. Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

6. College of Medicine, National Yang Ming Chiao Tung University, Yangming Campus, Taipei, Taiwan

7. Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan

8. Chinese Medicine Research Center, China Medical University, Taichung, Taiwan

9. Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan

10. Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan

11. Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

12. Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan

13. Department of Aquaculture, National Taiwan Ocean University, Keelung City, Taiwan

14. Center of Excellence for Ocean Engineering, National Taiwan Ocean University, Keelung City, Taiwan

15. Center of Excellence for the Oceans, National Taiwan Ocean University, Keelung City 20224, Taiwan

16. Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung City, Taiwan

17. Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung City, Taiwan

Abstract

Radiotherapy (RT) is currently only used in children with high-risk neuroblastoma (NB) due to concerns of long-term side effects as well as lack of effective adjuvant. Calreticulin (CALR) has served distinct physiological roles in cancer malignancies; nonetheless, impact of radiation on chaperones and molecular roles they play remains largely unknown. In present study, we systemically analyzed correlation between CALR and NB cells of different malignancies to investigate potential role of CALR in mediating radioresistance of NB. Our data revealed that more malignant NB cells are correlated to lower CALR expression, greater radioresistance, and elevated stemness as indicated by colony- and neurospheroid-forming abilities and vice versa. Of note, manipulating CALR expression in NB cells of varying endogenous CALR expression manifested changes in not only stemness but also radioresistant properties of those NB cells. Further, CALR overexpression resulted in greatly enhanced ROS and led to increased secretion of proinflammatory cytokines. Importantly, growth of NB tumors was significantly hampered by CALR overexpression and was synergistically ablated when RT was also administered. Collectively, our current study unraveled a new notion of utilizing CALR expression in malignant NB to diminish cancer stemness and mitigate radioresistance to achieve favorable therapeutic outcome for NB.

Funder

China Medical University, Taiwan

Publisher

Hindawi Limited

Subject

Cell Biology,Aging,General Medicine,Biochemistry

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