Retinoic acid amide inhibits JAK/STAT pathway in lung cancer which leads to apoptosis
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Small cell lung cancer (SCLC) accounts for 12 to 16 % of lung neoplasms and has a high rate of metastasis. The present study demonstrates the antiproliferative effect of retinoic acid amide in vitro and in vivo against human lung cancer cells. The results from MTT assay showed a significant growth inhibition of six tested lung cancer cell lines and inhibition of clonogenic growth at 30 μM. Retinoic acid amide also leads to G2/M-phase cell cycle arrest and apoptosis of lung cancer cells. It caused inhibition of JAK2, STAT3, and STAT5, increased the level of p21WAF1, and decreased cyclin A, cyclin B1, and Bcl-XL expression. Retinoic acid amide exhibited a synergistic effect on antiproliferative effects of methotrexate in lung cancer cells. In lung tumor xenografts, the tumor volume was decreased by 82.4 % compared to controls. The retinoic acid amide-treated tumors showed inhibition of JAK2/STAT3 activation and Bcl-XL expression. There was also increase in expression of caspase-3 and caspase-9 in tumors on treatment with retinoic acid amide. Thus, retinoic acid amide exhibits promising antiproliferative effects against human lung cancer cells in vitro and in vivo and enhances the antiproliferative effect of methotrexate.
KeywordsLung cancer Methotrexate Antiproliferative Metastasis STAT3 Dimerization
Conflicts of interest
Hong-Xing Li and Wei Zhao designed the study. Yan Shi, Ya-Na Li, Lian-Shuang Zhang, and Hong-Qin Zhang wrote the manuscript. Dong Wang and Hong-Xing Li performed the immunohistochemistry and the related statistical analysis. All authors approved the final version of the manuscript.
The project was financially supported by Shandong Province Natural Science Foundation (ZR2013HM047and 2011HL063) and Shandong Province Higher Education Technology Plan (J10LF57).
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