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Curcumin downregulates p38 MAPK-dependent X-ray repair cross-complement group 1 (XRCC1) expression to enhance cisplatin-induced cytotoxicity in human lung cancer cells

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Abstract

Cisplatin is a well-studied and widely used chemotherapeutic agent and is effective in the treatment of the advanced human non-small cell lung cancer (NSCLC). Curcumin is a yellow pigment derived from the rhizome of Curcuma longa and has been proved to have antioxidant and antitumor properties. XRCC1 is an important scaffold protein involved in base excision repair and plays an important role in the development of lung cancer. In this study, we characterize the role of curcumin in the cytotoxicity, p38 MAPK activation, and XRCC1 expression affected by cisplatin in NSCLC cells. We show that curcumin enhanced the cytotoxicity induced by cisplatin in two NSCLC cells, A549 and H1703. Treatment with cisplatin alone increased XRCC1 mRNA and protein expression through p38 MAPK activation. Moreover, SB2023580 (p38 inhibitor) decreased the XRCC1 mRNA and protein stability upon cisplatin treatment. Knockdown of XRCC1 in NSCLC cells by transfection of XRCC1 siRNA or inactivation of p38 MAPK resulted in enhancing the cytotoxicity and cell growth inhibition induced by cisplatin. Curcumin inhibited the expression of XRCC1 in cisplatin-exposed NSCLC cells. Furthermore, transfection with constitutive active MKK6 or HA-p38 MAPK vectors rescued the XRCC1 protein level and also the cell survival suppressed by cisplatin and curcumin combination in A549 and H1703 cells. These findings suggested that the downregulation of XRCC1 expression by curcumin can enhance the chemosensitivity of cisplatin in NSCLC cells.

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Abbreviations

CFA:

colony-forming ability

XRCC1:

X-ray repair cross-complement group 1

siRNA:

small interfering RNA

MAPK:

mitogen-activated protein kinase

NSCLC:

non-small cell lung cancer

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Acknowledgments

We thank Dr. Tsui-Chun Tsou, Dr. Show-Mei Chuang, and Dr. Jia-Ling Yang for providing us with expression plasmids for transfection.

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Authors and Affiliations

  1. Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan

    Chun-Liang Tung, Yi-Jun Jian & Kai-Sheng Liao

  2. Chang Gung University of Science and Technology, Chiayi, Taiwan

    Chun-Liang Tung

  3. Department of Food Science, National Chiayi University, Chiayi, Taiwan

    Jyh-Cheng Chen

  4. Department of Biochemical Science and Technology, National Chiayi University, 300 Syuefu Road, Chiayi, 600, Taiwan

    Tai-Jing Wang, Wen-Ching Chen, Hao-Yu Zheng, Po-Yuan Chang & Yun-Wei Lin

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  1. Chun-Liang Tung
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  2. Yi-Jun Jian
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  3. Jyh-Cheng Chen
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  4. Tai-Jing Wang
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  9. Yun-Wei Lin
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Correspondence to Yun-Wei Lin.

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Grant support

This study was funded by grants from the Ministry of Science and Technology, Taiwan, Grant MOST 104-2314-B-415-002 (Y-W. Lin) and Ditmanson Medical Foundation Chia-Yi Christian Hospital Research Program (R104-039).

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The authors declare that they have no conflict of interest.

Electronic supplementary material

Supplementary Fig. S1

Curcumin enhanced the cisplatin-induced cytotoxic effects of human fibroblasts HFW cells. Cisplatin and curcumin were combined at a ratio of 1:2 or 1:4 and the MTS assay was used to analyze cell viability. The results (mean ± SEM) were from three independent experiments. **P < 0.01, using the Student’s t test for the comparison between cells treated with cisplatin or curcumin alone or with curcumin–cisplatin cotreatment. (JPEG 756 kb)

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Tung, CL., Jian, YJ., Chen, JC. et al. Curcumin downregulates p38 MAPK-dependent X-ray repair cross-complement group 1 (XRCC1) expression to enhance cisplatin-induced cytotoxicity in human lung cancer cells. Naunyn-Schmiedeberg's Arch Pharmacol 389, 657–666 (2016). https://doi.org/10.1007/s00210-016-1235-5

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  • DOI: https://doi.org/10.1007/s00210-016-1235-5

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