Retinoic acid amide inhibits JAK/STAT pathway in lung cancer which leads to apoptosis
- 317 Downloads
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).
- 22.Mologni L, Ponzanelli I, Bresciani F, Sardiello G, Bergamaschi D, Gianni M, et al. The novel synthetic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphtalene carboxylic acid (CD437) causes apoptosis in acute promyelocytic leukemia cells through rapid activation of caspases. Blood. 1999;93:1045–61.PubMedGoogle Scholar
- 29.Rotan R. Retinoids as modulators of tumor cell invasion and metastasis. Semin Cancer Biol. 1991;2:197–208.Google Scholar
- 32.Sahu RP, Srivastava SK. The role of STAT-3 in the induction of apoptosis in pancreatic cancer cells by benzyl isothiocyanate. J Natl Cancer Inst. 2009;101:176–93.Google Scholar
- 35.Adnane J, Bizouarn FA, Qian Y, Hamilton AD, Sebti SM. p21(WAF1/CIP1) is upregulated by the geranylgeranyltransferase I inhibitor GGTI-298 through a transforming growth factor h- and Sp1-responsive element: involvement of the small GTPaseRhoA. Mol Cell Biol. 1998;18:6962–70.CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Bai J, Sui J, Demirjian A, Vollmer Jr CM, Marasco W, Callery MP. Predominant Bcl-XL knockdown disables antiapoptotic mechanisms: tumor necrosis factor-related apoptosis-inducing ligand-based triple chemotherapy overcomes chemoresistance in pancreatic cancer cells in vitro. Cancer Res. 2005;65:2344–52.CrossRefPubMedGoogle Scholar