Oncotarget

Research Papers:

Theophylline exhibits anti-cancer activity via suppressing SRSF3 in cervical and breast cancer cell lines

Yung-Lung Chang, Yu-Juei Hsu _, Ying Chen, Yi-Wen Wang and Shih-Ming Huang

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Oncotarget. 2017; 8:101461-101474. https://doi.org/10.18632/oncotarget.21464

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Abstract

Yung-Lung Chang1, Yu-Juei Hsu1,2, Ying Chen1, Yi-Wen Wang3 and Shih-Ming Huang1

1Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, Republic of China

2Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China

3Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan, Republic of China

Correspondence to:

Yu-Juei Hsu, email: yujuei@mail2000.com.tw

Shih-Ming Huang, email: shihming@ndmctsgh.edu.tw

Keywords: methylxanthine, caffeine, theophylline, SRSF3, p53

Received: April 11, 2017     Accepted: September 18, 2017     Published: October 03, 2017

ABSTRACT

Caffeine, theophylline, and theobromine are the most well-known members of methylxanthines. Caffeine-induced serine/arginine-rich splicing factor 2, SRSF2, and SRSF3 are required for the alternative splicing of a subset of cancer-associated genes. However, it remains to be investigated whether and how theophylline and theobromine as well as caffeine exert their antitumor effects through mediating the alternative splicing process. Here, we reveal that theophylline down-regulated SRSF3 expression and switched p53 from alpha into a beta isoform as caffeine did in HeLa and MCF-7 cells via the reverse-transcriptase polymerase chain reaction and Western blot analysis. Further functional studies show that theophylline induced cellular apoptosis, senescence, and decreased colony formation. Interestingly, theophylline had a suppressive effect on cellular proliferation, whereas caffeine enhanced cellular proliferation rates via the 5-bromo-2-deoxyuridine analysis. Theophylline and caffeine had no effect on MCF-10A cells, which is a normal breast cell line. Our results provide an insight that theophylline as well as caffeine could be repurposed as antitumor leading compounds via the downregulation of splicing factor SRSF3 and its target genes.


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