Original articles
Hong Zhang, Liyan Huang, Liyang Tao, Jianye Zhang, Fang Wang, Xu Zhang, Liwu Fu. Secalonic acid D induces cell apoptosis in both sensitive and ABCG2-overexpressing multidrug resistant cancer cells through upregulating c-Jun expression[J]. Acta Pharmaceutica Sinica B, 2019, 9(3): 516-525

Secalonic acid D induces cell apoptosis in both sensitive and ABCG2-overexpressing multidrug resistant cancer cells through upregulating c-Jun expression
Hong Zhanga, Liyan Huanga, Liyang Taoa, Jianye Zhangb, Fang Wanga, Xu Zhanga, Liwu Fua
a Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou 510060, China;
b School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China
Secalonic acid D (SAD) could inhibit cell growth in not only sensitive cells but also multidrug resistant (MDR) cells. However, the molecular mechanisms need to be elucidated. Here, we identified that SAD possessed potent cytotoxicity in 3 pairs of MDR and their parental sensitive cells including S1-MI-80 and S1, H460/MX20 and H460, MCF-7/ADR and MCF-7 cells. Furthermore, SAD induced cell G2/M phase arrest via the downregulation of cyclin B1 and the increase of CDC2 phosphorylation. Importantly, JNK pathway upregulated the expression of c-Jun in protein level and increased c-Jun phosphorylation induced by SAD, which was linked to cell apoptosis via c-Jun/Src/STAT3 pathway. To investigate the mechanisms of upregulation of c-Jun protein by SAD, the mRNA expression level and degradation of c-Jun were examined. We found that SAD did not alter the mRNA level of c-Jun but inhibited its proteasome-dependent degradation. Taken together, these results implicate that SAD induces cancer cell death through c-Jun/Src/STAT3 signaling axis by inhibiting the proteasome-dependent degradation of c-Jun in both sensitive cells and ATP-binding cassette transporter sub-family G member 2 (ABCG2)-mediated MDR cells.
Key words:    Multidrug resistance    Secalonic acid D    Apoptosis    c-Jun    ABCG2   
Received: 2018-09-30     Revised:
DOI: 10.1016/j.apsb.2018.12.006
Funds: This work was supported by grants from the National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program" (No. 2018ZX09711002, China), Science and Technology Foundation of Guangdong Province (No. 2016A030312014, China), Guangzhou Science and Technology Program (No. 201707010048, China) and from the Scientific and Technological Leading Talent Project of Guangdong Province (2015, China).
Corresponding author: Liwu Fu     Email:Fulw@mail.sysu.edu.cn
Author description:
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Hong Zhang
Liyan Huang
Liyang Tao
Jianye Zhang
Fang Wang
Xu Zhang
Liwu Fu

1. Simmons TL, Andrianasolo E, McPhail K, Flatt P, Gerwick WH. Marine natural products as anticancer drugs. Mol Cancer Ther 2005;4:333-42.
2. Glaser KB, Mayer AM. A renaissance in marine pharmacology:from preclinical curiosity to clinical reality. Biochem Pharmacol 2009;78:440-8.
3. Bian J, Song F, Zhang L. Strategies on the construction of high-quality microbial natural product library-a review. Acta Microbiol Sin 2008;48:1132-7.
4. Guo Z, She Z, Shao C, Wen L, Liu F, Zheng Z, et al. 1H and 13C NMR signal assignments of paecilin A and B, two new chromone derivatives from mangrove endophytic fungus Paecilomyces sp. (tree 1-7). Magn Reson Chem 2007;45:777-80.
5. Zhang JY, Tao LY, Liang YJ, Yan YY, Dai CL, Xia XK, et al. Secalonic acid D induced leukemia cell apoptosis and cell cycle arrest of G1 with involvement of GSK-3β/β-catenin/c-Myc pathway. Cell Cycle 2009;8:2444-50.
6. Hu YP, Tao LY, Wang F, Zhang JY, Liang YJ, Fu LW. Secalonic acid D reduced the percentage of side populations by down-regulating the expression of ABCG2. Biochem Pharmacol 2013;85:1619-25.
7. Qi XM, Wang F, Mortensen M, Wertz R, Chen G. Targeting an oncogenic kinase/phosphatase signaling network for cancer therapy. Acta Pharm Sin B 2018;8:511-7.
8. Sui H, Zhou S, Wang Y, Liu X, Zhou L, Yin P, et al. COX-2 contributes to P-glycoprotein-mediated multidrug resistance via phosphorylation of c-Jun at Ser63/73 in colorectal cancer. Carcinogenesis 2011;32:667-75.
9. Tomiyasu H, Watanabe M, Sugita K, Goto-Koshino Y, Fujino Y, Ohno K, et al. Regulations of ABCB1 and ABCG2 expression through MAPK pathways in acute lymphoblastic leukemia cell lines. Anticancer Res 2013;33:5317-23.
10. Bohmann D, Bos TJ, Admon A, Nishimura T, Vogt PK, Tjian R. Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1. Science 1987;238:1386-92.
11. Karin M, Hawkins PT, Irvine RF, Michell RH, Marshall CJ. The regulation of AP-1 activity by mitogen-activated protein kinases. Philos Trans Roy Soc Lond Ser B Biol Sci 1996;351:127-34.
12. Kollmann K, Heller G, Sexl V. c-JUN prevents methylation of p16INK4a (and Cdk6):the villain turned bodyguard. Oncotarget 2011;2:422-7.
13. Ishdorj G, Johnston JB, Gibson SB. Cucurbitacin-I (JSI-124) activates the JNK/c-Jun signaling pathway independent of apoptosis and cell cycle arrest in B leukemic cells. BMC Cancer 2011;11:268.
14. Tao LY, Liang YJ, Wang F, Chen LM, Yan YY, Dai CL, et al. Cediranib (recentin, AZD2171) reverses ABCB1-and ABCC1-mediated multidrug resistance by inhibition of their transport function. Cancer Chemother Pharmacol 2009;64:961-9.
15. Dhulipala VC, Welshons WV, Reddy CS. Inhibition of human embryonic palatal mesenchymal cell cycle by secalonic acid D:a probable mechanism of its cleft palate induction. Orthod Craniofac Res 2004;7:227-36.
16. Sui H, Cai GX, Pan SF, Deng WL, Wang YW, Chen ZS, et al. miR200c attenuates P-gp-mediated MDR and metastasis by targeting JNK2/c-Jun signaling pathway in colorectal cancer. Mol Cancer Ther 2014;13:3137-51.
17. Eferl R, Wagner EF. AP-1:a double-edged sword in tumorigenesis. Nat Rev Cancer 2003;3:859-68.
18. Chatterjee M, Ben-Josef E, Thomas DG, Morgan MA, Zalupski MM, Khan G, et al. Caveolin-1 is associated with tumor progression and confers a multi-modality resistance phenotype in pancreatic cancer. Sci Rep 2015;5:10867.
19. Fenical W. New pharmaceuticals from marine organisms. Trends Biotechnol 1997;15:339-41.
20. Hu X, Zhang Z, Liu T, Song L, Zhu J, Guo Z, et al. Polypeptide Fraction from Arca subcrenata induces apoptosis and G2/M phase arrest in Hela cells via ROS-mediated MAPKs pathways. Evid Based Complement Altern Med 2015;2015:930249.
21. Farooqi AA, Fayyaz S, Hou MF, Li KT, Tang JY, Chang HW. Reactive oxygen species and autophagy modulation in non-marine drugs and marine drugs. Mar Drugs 2014;12:5408-24.
22. Guru SK, Pathania AS, Kumar S, Ramesh D, Kumar M, Rana S, et al. Secalonic acid-D represses HIF1α/VEGF-mediated angiogenesis by regulating the Akt/mTOR/p70S6K signaling cascade. Cancer Res 2015;75:2886-96.
23. An X, Sarmiento C, Tan T, Zhu H. Regulation of multidrug resistance by microRNAs in anti-cancer therapy. Acta Pharm Sin B 2017;7:38-51.
24. Cho YC, Park JE, Park BC, Kim JH, Jeong DG, Park SG, et al. Cell cycle-dependent Cdc25C phosphatase determines cell survival by regulating apoptosis signal-regulating kinase 1. Cell Death Differ 2015;22:1605-17.
25. Liao YJ, Bai HY, Li ZH, Zou J, Chen JW, Zheng F, et al. Longikaurin A, a natural ent-kaurane, induces G2/M phase arrest via downregulation of SKP2 and apoptosis induction through ROS/JNK/c-Jun pathway in hepatocellular carcinoma cells. Cell Death Dis 2014;5:e1137.
26. Zhang J, Zhu X, Li H, Li B, Sun L, Xie T, et al. Piperine inhibits proliferation of human osteosarcoma cells via G2/M phase arrest and metastasis by suppressing MMP-2/-9 expression. Int Immunopharmacol 2015;24:50-8.
27. Alam SK, Yadav VK, Bajaj S, Datta A, Dutta SK, Bhattacharyya M, et al. DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53. Cell Death Differ 2016;23:707-22.
28. Zhu MM, Tong JL, Xu Q, Nie F, Xu XT, Xiao SD, et al. Increased JNK1 signaling pathway is responsible for ABCG2-mediated multidrug resistance in human colon cancer. PLoS One 2012;7:e41763.
29. Huang CH, Chen YJ, Chao TY, Liu WH, Changchien JJ, Hu WP, et al. The association between p38 MAPK-mediated TNF-α/TNFR2 up-regulation and 2-(4-aminophenyl)-7-methoxybenzothiazoleinduced apoptosis in human leukemia U937 cells. J Cell Physiol 2016;231:130-41.
30. Whang YM, Jin SB, Park SI, Chang IH. MEK inhibition enhances efficacy of bacillus Calmette-Guérin on bladder cancer cells by reducing release of Toll-like receptor 2-activated antimicrobial peptides. Oncotarget 2017;8:53168-79.
31. Musti AM, Treier M, Bohmann D. Reduced ubiquitin-dependent degradation of c-Jun after phosphorylation by MAP kinases. Science 1997;275:400-2.
32. Zhang J, Zhu F, Li X, Dong Z, Xu Y, Peng C, et al. Rack1 protects Nterminal phosphorylated c-Jun from Fbw7-mediated degradation. Oncogene 2012;31:1835-44.
33. Marsolier J, Perichon M, DeBarry JD, Villoutreix BO, Chluba J, Lopez T, et al. Theileria parasites secrete a prolyl isomerase to maintain host leukocyte transformation. Nature 2015;520:378-82.
34. Kim JH, Lee Y, Kim MY, Cho JY. 4-(Tert-butyl)-2,6-bis(1-phenylethyl)phenol induces pro-apoptotic activity. Korean J Physiol Pharmacol 2016;20:253-9.
35. Turkson J, Bowman T, Adnane J, Zhang Y, Djeu JY, Sekharam M, et al. Requirement for Ras/Rac1-mediated p38 and c-Jun N-terminal kinase signaling in Stat3 transcriptional activity induced by the Src oncoprotein. Mol Cell Biol 1999;19:7519-28.
36. La Fortezza M, Schenk M, Cosolo A, Kolybaba A, Grass I, Classen AK. JAK/STAT signalling mediates cell survival in response to tissue stress. Development 2016;143:2907-19.
37. Wang SW, Chen YR, Chow JM, Chien MH, Yang SF, Wen YC, et al. Stimulation of Fas/FasL-mediated apoptosis by luteolin through enhancement of histone H3 acetylation and c-Jun activation in HL-60 leukemia cells. Mol Carcinog 2018;57:866-77.
38. Tomicic MT, Meise R, Aasland D, Berte N, Kitzinger R, Krämer OH, et al. Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM. Oncotarget 2015;6:33755-68.
39. Song B, Xie B, Wang C, Li M. Caspase-3 is a target gene of c-Jun:ATF2 heterodimers during apoptosis induced by activity deprivation in cerebellar granule neurons. Neurosci Lett 2011;505:76-81.
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