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  1. bookVolume 71 (2021): Issue 2 (June 2021)
Acta Pharmaceutica's Cover Image
Acta Pharmaceutica
Journal Details
License
Format
Journal
First Published
28 Feb 2007
Publication timeframe
4 times per year
Languages
English
access type Open Access

Norcantharidin induces G2/M arrest and apoptosis via activation of ERK and JNK, but not p38 signaling in human renal cell carcinoma ACHN cells

Shuaishuai Huang
Gulimire Tuergong
Hangjie Zhu
Xue Wang
Guobin Weng
Yu Ren
Published Online: 04 Nov 2020
Page range: 267 - 278
Accepted: 15 Apr 2020
Journal Details
License
Format
Journal
First Published
28 Feb 2007
Publication timeframe
4 times per year
Languages
English
Abstract

Renal cell carcinoma (RCC) is generally acknowledged as the most resistant primary malignancy unresponsive to conventional radiotherapy and chemotherapy treatments. Norcantharidin (NCTD), a therapeutic compound derived from medicinal plants, has been shown to trigger apoptosis, as well as antimetastatic and antioxidant activities in several tumor cells. However, NCTD’s mechanism of antitumor activity in the RCC cell line remains unclear. In this study, we report that NCTD led to a time- and dose-dependent inhibition of cell proliferation. It had also markedly induced apoptosis and G2/M phase cell cycle arrest in a dose-dependent manner by decreasing the expressions of pro-caspase-3, pro-caspase-9, cyclin B1, and pCDC25C while increasing active caspase-3, cleaved-PARP, P21, and pCDC2 levels. Interestingly, NCTD treatment provoked the phosphorylation of extracellular-regulated protein kinase (ERK) and c-Jun-N-terminal kinase (JNK), but not of p38 MAPK. Moreover, SCH772984 and SP600125, ERK and JNK inhibitors, respectively, could partially abolish NCTD-induced apoptosis and G2/M phase cell cycle arrest. Collectively, these findings suggest that NCTD might activate JNK and ERK signaling pathways, consequently inducing apoptosis and G2/M arrest through the modulation of related proteins. This study provided evidence that NCTD is a promising therapeutic drug for the treatment of RCC.

Keywords

  • norcantharidin
  • renal cancer cells
  • ERK
  • JNK
  • p38 MAPK
  • apoptosis
  • cell cycle arrest

1. R. L. Siegel, K. D. Miller and A. Jemal, Cancer statistics, CA Cancer J. Clin.68 (2018) 7–30; https://doi.org/10.3322/caac.2144210.3322/caac.21442Search in Google Scholar

2. M. Sun, G. Lughezzani, P. Perrotte and P. I. Karakiewicz, Treatment of metastatic renal cell carcinoma, Nat. Rev. Urol.7 (2010) 327–338; https://doi.org/10.1038/nrurol.2010.5710.1038/nrurol.2010.57Search in Google Scholar

3. X. Wang, Y. Ren, H. Zhuang, X. Meng, S. Huang, Y. Li, M. Hehir and P. Wang, Decrease of phosphorylated proto-oncogene CREB at Ser 133 site inhibits growth and metastatic activity of renal cell cancer, Expert Opin. Ther. Targets19 (2015) 985–995; https://doi.org/10.1517/14728222.2015.105320810.1517/14728222.2015.1053208Search in Google Scholar

4. W. W. An, X. F. Gong, M. W. Wang, S. Tashiro, S. Onodera and T. Ikejima, Norcantharidin induces apoptosis in HeLa cells through caspase, MAPK, and mitochondrial pathways, Acta Pharmacol. Sin.25 (2004) 1502–1508; https://doi.org/10.1016/S0898-6568(03)00096-210.1016/S0898-6568(03)00096-2Search in Google Scholar

5. Y. Ren, S. W. Zhang, Z. H. Xie, X. M. Xu, L. L. Chen, Z. G. Lou, G. B. Weng and X. P. Yao, Cantharidin induces G2/M arrest and triggers apoptosis in renal cell carcinoma, Mol. Med. Rep.14 (2016) 5614–5618; https://doi.org/10.3892/mmr.2016.596310.3892/mmr.2016.5963Search in Google Scholar

6. M. N. Jahnke, S. Hwang, J. L. Griffith and T. Shwayder, Cantharidin for treatment of facial molluscum contagiosum: A retrospective review, J. Am. Acad. Dermatol.78 (2018) 198–200; https://doi.org/10.1016/j.jaad.2017.08.04410.1016/j.jaad.2017.08.044Search in Google Scholar

7. F. Massicot, H. Dutertre-Catella, C. Pham-Huy, X. H. Liu, H. T. Duc and J. M. Warnet, In vitro assessment of renal toxicity and inflammatory events of two protein phosphatase inhibitors cantharidin and nor-cantharidin, Basic Clin. Pharmacol. Toxicol.96 (2005) 26–32; https://doi.org/10.1111/j.1742-7843.2005.pto960104.x10.1111/j.1742-7843.2005.pto960104.xSearch in Google Scholar

8. S. H. Kok, S. J. Cheng, C. Y. Hong, J. J. Lee, S. K. Lin, Y. S. Kuo, C. P. Chiang and M. Y. Kuo, Norcantharidin-induced apoptosis in oral cancer cells is associated with an increase of proapoptotic to antiapoptotic protein ratio, Cancer Lett.217 (2005) 43–52; https://doi.org/10.1016/j.canlet.2004.07.04510.1016/j.canlet.2004.07.045Search in Google Scholar

9. C. H. Hsia, W. J. Lu, K. H. Lin, D. S. Chou, P. Geraldine, T. Jayakuma, N. C. Chang and J. R. Sheu, Norcantharidin, a clinical used chemotherapeutic agent, acts as a powerful inhibitor by interfering with fibrinogen-integrin alphaIIb beta3 binding in human platelets, J. Cell Mol. Med.22 (2018) 2142–2152; https://doi.org/10.1111/jcmm.1348810.1111/jcmm.13488Search in Google Scholar

10. Y. Li, Q. Chen, F. Y. Liu, Y. M. Peng, T. Hou, S. B. Duan, J. Li, J. H. Luo, L. Sun and G. H. Ling, Norcantharidin attenuates tubulointerstitial fibrosis in rat models with diabetic nephropathy, Ren. Fail.33 (2011) 233–241; https://doi.org/10.3109/0886022X.2011.55330510.3109/0886022X.2011.553305Search in Google Scholar

11. T. Yu, F. Hou, M. Liu, L. Zhou, D. Li, J. Liu, Z. Fan and Q. Li, Norcantharidin anti-angiogenesis activity possibly through an endothelial cell pathway in human colorectal cancer, Asian Pac. J. Cancer Prev.13 (2012) 499–503; https://doi.org/10.7314/APJCP.2012.13.2.49910.7314/APJCP.2012.13.2.499Search in Google Scholar

12. H. Lv, Y. Li, H. Du, J. Fang, X. Song and J. Zhang, The synthetic compound norcantharidin induced apoptosis in mantle cell lymphoma in vivo and in vitro through the PI3K-Akt-NF- kappa B signaling pathway, Evid. Based Complement Alternat. Med.2013 (2013) 461487; https://doi.org/10.1155/2013/46148710.1155/2013/461487Search in Google Scholar

13. Q. Y. Zhang, X. Q. Yue, Y. P. Jiang, T. Han and H. L. Xin, FAM46C is critical for the anti-proliferation and pro-apoptotic effects of norcantharidin in hepatocellular carcinoma cells, Sci. Rep.7 (2017) 396; https://doi.org/10.1038/s41598-017-00313-610.1038/s41598-017-00313-6Search in Google Scholar

14. P. Y. Yang, M. F. Chen, Y. H. Kao, D. N. Hu, F. R. Chang and Y. C. Wu, Norcantharidin induces apoptosis of breast cancer cells: involvement of activities of mitogen activated protein kinases and signal transducers and activators of transcription, Toxicol. In Vitro25 (2011) 699–707; https://doi.org/10.1016/j.tiv.2011.01.01110.1016/j.tiv.2011.01.011Search in Google Scholar

15. C. L. Lin, C. M. Chen, C. L. Lin, C. W. Cheng, C. H. Lee and Y. H. Hsieh, Norcantharidin induces mitochondrial-dependent apoptosis through Mcl-1 inhibition in human prostate cancer cells, Biochim. Biophys. Acta1864 (2017) 1867–1876; https://doi.org/10.1016/j.bbamcr.2017.07.01510.1016/j.bbamcr.2017.07.015Search in Google Scholar

16. Z. Wang, D. You, M. Lu, Y. He and S. Yan, Inhibitory effect of norcantharidin on melanoma tumor growth and vasculogenic mimicry by suppressing MMP-2 expression, Oncol. Lett.13 (2017) 1660–1664; https://doi.org/10.3892/ol.2017.562210.3892/ol.2017.5622Search in Google Scholar

17. M. Y. Huang, L. L. Zhang, J. Ding and J. J. Lu, Anticancer drug discovery from Chinese medicinal herbs, Chin. Med.13 (2018) 35; https://doi.org/10.1186/s13020-018-0192-y10.1186/s13020-018-0192-ySearch in Google Scholar

18. A. A. Nagle, F. F. Gan, G. Jones, C. L. So, G. Wells and E. H. Chew, Induction of tumor cell death through targeting tubulin and evoking dysregulation of cell cycle regulatory proteins by multi-functional cinnamaldehydes, PLoS One7 (2012) e50125; https://doi.org/10.1371/journal.pone.005012510.1371/journal.pone.0050125Search in Google Scholar

19. S. C. Biswas, P. Sanphui, N. Chatterjee, S. Kemeny and L. A. Greene, Cdc25A phosphatase: a key cell cycle protein that regulates neuron death in disease and development, Cell Death Dis.8 (2017) e2692; https://doi.org/10.1038/cddis.2017.11510.1038/cddis.2017.115Search in Google Scholar

20. J. Wang and Y. F. Jiang, Natural compounds as anticancer agents: Experimental evidence, World J. Exp. Med.2 (2012) 45–57; https://doi.org/10.5493/wjem.v2.i3.4510.5493/wjem.v2.i3.45Search in Google Scholar

21. N. Bailon-Moscoso, G. Cevallos-Solorzano, J. C. Romero-Benavides and M. I. Orellana, Natural compounds as modulators of cell cycle arrest: Application for anticancer chemotherapies, Curr. Genomics.18 (2017) 106–131; https://doi.org/10.2174/138920291766616080812564510.2174/1389202917666160808125645Search in Google Scholar

22. M. Brentnall, L. Rodriguez-Menocal, R. L. De Guevara, E. Cepero and L. H. Boise, Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis, BMC Cell Biol.14 (2013) 32; https://doi.org/10.1186/1471-2121-14-3210.1186/1471-2121-14-32Search in Google Scholar

23. J. Kale, E. J. Osterlund and D. W. Andrews, BCL-2 family proteins: changing partners in the dance towards death, Cell Death Differ.25 (2018) 65–80; https://doi.org/10.1038/cdd.2017.18610.1038/cdd.2017.186Search in Google Scholar

24. W. W. Chu, X. Y. He, A. L. Yan, S. W. Wang, S. Li, S. Nian, Y. L. Wang and F. L. Liang, Ischemic postconditioning lightening ischemia/reperfusion apoptosis of rats via mitochondria pathway, Eur. Rev. Med. Pharmacol. Sci.23 (2019) 6307–6314; https://doi.org/10.26355/eurrev_201907_18453Search in Google Scholar

25. H. K. An, K. M. Chung, H. Park, J. Hong, J. E. Gim, H. Choi, Y. W. Lee, J. Choi, J. Y. Mun and S. W. Yu, CASP9 (caspase 9) is essential for autophagosome maturation through regulation of mitochondrial homeostasis, Autophagy (2019) 1–20; https://doi.org/10.1080/15548627.2019.169539810.1080/15548627.2019.1695398Search in Google Scholar

26. C. L. Cusack, V. Swahari, W. H. Henley, J. M. Ramsey and M. Deshmukh, Distinct pathways mediate axon degeneration during apoptosis and axon-specific pruning, Nat. Commun.4 (2013) 1876; https://doi.org/10.1038/ncomms291010.1038/ncomms2910Search in Google Scholar

27. G. Pearson, F. Robinson, T. Beers Gibson, B. E. Xu, M. Karandikar, K. Berman and M. H. Cobb, Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions, Endocr. Rev.22 (2001) 153–183; https://doi.org/10.1210/edrv.22.2.042810.1210/edrv.22.2.0428Search in Google Scholar

28. Y. Sun, W. Z. Liu, T. Liu, X. Feng, N. Yang and H. F. Zhou, Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis, J. Recept. Signal Transduct. Res.35 (2015) 600–604; https://doi.org/10.3109/10799893.2015.103041210.3109/10799893.2015.1030412Search in Google Scholar

29. T. Chen and Y. S. Wong, Selenocystine induces S-phase arrest and apoptosis in human breast adenocarcinoma MCF-7 cells by modulating ERK and Akt phosphorylation, J. Agric. Food Chem.56 (2008) 10574–10581; https://doi.org/10.1021/jf802125t10.1021/jf802125tSearch in Google Scholar

30. W. Liu, R. Ning, R. N. Chen, X. F. Huang, Q. S. Dai, J. H. Hu, Y. W. Wang, L. L. Wu, J. Xiong, G. Hu, Q. L. Guo, J. Yang and H. Wang, Aspafilioside B induces G2/M cell cycle arrest and apoptosis by up-regulating H-Ras and N-Ras via ERK and p38 MAPK signaling pathways in human hepatoma HepG2 cells, Mol. Carcinog.55 (2016) 440–457; https://doi.org/10.1002/mc.2229310.1002/mc.22293Search in Google Scholar

31. Y. Tsuchiya, S. Murai and S. Yamashita, Dual inhibition of Cdc2 protein kinase activation during apoptosis in Xenopus egg extracts, FEBS J.282 (2015) 1256–1270; https://doi.org/10.1111/febs.1321710.1111/febs.13217Search in Google Scholar

32. W. J. Sun, H. Huang, B. He, D. H. Hu, P. H. Li, Y. J. Yu, X. H. Zhou, Z. Lv, L. Zhou, T. Y. Hu, Z. C. Yao, M. D. Lu, X. Shen and Z. Q. Zheng, Romidepsin induces G2/M phase arrest via Erk/cdc25C/cdc2/cyclinB pathway and apoptosis induction through JNK/c-Jun/caspase3 pathway in hepato-cellular carcinoma cells, Biochem. Pharmacol.127 (2017) 90–100; https://doi.org/10.1016/j.bcp.2016.12.00810.1016/j.bcp.2016.12.008Search in Google Scholar

33. X. Grana and E. P. Reddy, Cell cycle control in mammalian cells: role of cyclins, cyclin-dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs), Oncogene11 (1995) 211–219.Search in Google Scholar

34. N. Kaushal and M. P. Bansal, Inhibition of CDC2/Cyclin B1 in response to selenium-induced oxidative stress during spermatogenesis: potential role of Cdc25c and p21, Mol. Cell Biochem.298 (2007) 139–150; https://doi.org/10.1007/s11010-006-9360-y10.1007/s11010-006-9360-ySearch in Google Scholar

35. Y. C. Cho, J. E. Park, B. C. Park, J. H. Kim, D. G. Jeong, S. G. Park and S. Cho, Cell cycle-dependent Cdc25C phosphatase determines cell survival by regulating apoptosis signal-regulating kinase 1, Cell Death Differ.22 (2015) 1605–1617; https://doi.org/10.1038/cdd.2015.210.1038/cdd.2015.2Search in Google Scholar

36. Y. S. Sun, L. X. Lv, Z. Zhao, X. He, L. You, J. K. Liu and Y. Q. Li, Cordycepol C induces caspase-independent apoptosis in human hepatocellular carcinoma HepG2 cells, Biol. Pharm. Bull.37 (2014) 608–617; https://doi.org/10.1248/bpb.b13-0087710.1248/bpb.b13-00877Search in Google Scholar

37. M. Gaestel, MAPK-activated protein kinases (MKs): Novel insights and challenges, Front Cell Dev. Biol.3 (2015) 88; https://doi.org/10.3389/fcell.2015.0008810.3389/fcell.2015.00088Search in Google Scholar

38. Z. Han, B. Li, J. Wang, X. Zhang, Z. Li, L. Dai, M. Cao and J. Jiang, Norcantharidin inhibits SK-NSH neuroblastoma cell growth by induction of autophagy and apoptosis, Technol. Cancer Res. Treat.16 (2017) 33–44; https://doi.org/10.1177/153303461562458310.1177/1533034615624583Search in Google Scholar

39. Y. N. Chen, C. C. Cheng, J. C. Chen, W. Tsauer and S. L. Hsu, Norcantharidin-induced apoptosis is via the extracellular signal-regulated kinase and c-Jun-NH2-terminal kinase signaling pathways in human hepatoma HepG2 cells, Br. J. Pharmacol.140 (2003) 461–470; https://doi.org/10.1038/sj.bjp.070546110.1038/sj.bjp.0705461Search in Google Scholar

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