新型蛋白酶体抑制剂YSY-01A诱导PC-3M细胞自噬的作用

doi:10.5246/jcps.2014.08.073

中国药学(英文版)

新型蛋白酶体抑制剂YSY-01A诱导PC-3M细胞自噬的作用

王喆¹, 袁霞¹, 葛泽梅², 冉福香¹, 吴军¹, 李润涛^2*, 崔景荣^1*

1. 北京大学医学部天然药物及仿生药物国家重点实验室, 北京 100191
2. 北京大学医学部药学院化学生物学系, 北京 100191

收稿日期:2014-05-04 修回日期:2014-05-14 出版日期:2014-08-31 发布日期:2014-06-01
通讯作者: Tel.: 86-10-82802467, 86-10-82801504
基金资助:
Eleventh FiveYear Plan for National Science and Technology Major Project (Grant No. 2009ZX0930010), National Science Foundation of China (Grant No. 81172915) and a grant from Major New Drugs Research and Development Platform of Peking University (Grant No. 2009ZX09301010).

A new proteasome inhibitor YSY-01A induced autophagy in PC-3M cells

Zhe Wang¹, Xia Yuan¹, Zemei Ge², Fuxiang Ran¹, Jun Wu¹, Runtao Li^2*, Jingrong Cui^1*

1. State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China
2. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2014-05-04 Revised:2014-05-14 Online:2014-08-31 Published:2014-06-01
Contact: Tel.: 86-10-82802467, 86-10-82801504
Supported by:
Eleventh FiveYear Plan for National Science and Technology Major Project (Grant No. 2009ZX0930010), National Science Foundation of China (Grant No. 81172915) and a grant from Major New Drugs Research and Development Platform of Peking University (Grant No. 2009ZX09301010).

摘要/Abstract

摘要：

在前期研究中, YSY-01A通过抑制蛋白酶体活性, 对多种肿瘤细胞表现出增殖抑制作用。但是, YSY-01A对于与蛋白酶体途径有着密切联系的自噬系统的影响目前还不清楚。本文研究目的是探讨YSY-01A对自噬的影响与分子机制。研究结果表明, YSY-01A能够显著抑制PC-3M细胞的增殖 (P<0.001, IC₅₀= 287 nM, 48 h), 并且该抑制作用具有时间依赖性与浓度依赖性。YSY-01A (400 nM)能够在短时间内诱导PC-3M细胞自噬, 12 h后自噬活动步入末期。分子实验结果表明, YSY-01A能够明显促进P53蛋白的磷酸化、抑制mTOR的活化, 上调Beclin-1与LC3的表达。而在抑制自噬后, 可增加PC-3M细胞对YSY-01A的敏感性。总之, YSY-01A可抑制PC-3M细胞增殖, 并能够诱导PC-3M细胞自噬, 自噬在12 h后步入末期, 抑制自噬后, 可增强YSY-01A对PC-3M细胞的增殖抑制作用。

关键词: 蛋白酶体抑制剂, YSY-01A, PC-3M, 自噬

Abstract:

YSY-01A has shown proliferation inhibitory activity to certain types of tumor cells by inhibiting proteasome. However, its effect on autophagy, which is related with the ubiquitin proteasome pathway (UPP), remains unclear. Our study aimed to find out its effect on autophagy and possible molecular mechanisms. The results suggested that YSY-01A significantly (P<0.001) inhibited proliferation of PC-3M cells (IC₅₀ was 287 nM for 48 h) in a concentration-dependent and time-dependent manner. YSY-01A (100 nM, 3 h) also induced autophagy in PC-3M cells through increasing the expression of P53 (P<0.001), Beclin-1 (P<0.001) and LC3 (P<0.001), and decreasingthe expression of p-mTOR (P<0.001) as compared with the negative control group. Autophagy stayed at a final stage in PC-3M cells after treated with YSY-01A(400 nM)for 12 h. Meanwhile inhibition of autophagy with chloroquine increased the sensitivity to YSY-01A in PC-3M cells. In conclusion, YSY-01A showed high proliferation inhibitory activity of PC-3M cells and it could induce autophagy in PC-3M cells. Inhibiting autophagy increased the cytotoxic activity of YSY-01A in PC-3M cells.

Key words: Proteasome inhibitor, YSY-01A, PC-3M, Autophagy

中图分类号:

R962

Supporting:

王喆, 袁霞, 葛泽梅, 冉福香, 吴军, 李润涛, 崔景荣. 新型蛋白酶体抑制剂YSY-01A诱导PC-3M细胞自噬的作用[J]. 中国药学(英文版), DOI: 10.5246/jcps.2014.08.073.

Zhe Wang, Xia Yuan, Zemei Ge, Fuxiang Ran, Jun Wu, Runtao Li, Jingrong Cui. A new proteasome inhibitor YSY-01A induced autophagy in PC-3M cells[J]. Journal of Chinese Pharmaceutical Sciences, DOI: 10.5246/jcps.2014.08.073.

参考文献

[1] Tamotsu, Y. Biochem. Bioph. RES. CO. 2004, 313, 453-458.

[2] Kyeong, S.C. Exp. Mol. Med. 2012, 44, 109-120.

[3] Jia, X.; Yuan X.; Chu, M.; Ran, F.X.; Li, R.T.; Cui, J.R. J. Chin. Pharm. Sci. 2013, 22, 483-490.

[4] Tong, K.; Liu, J.T.; Yuan, X.; Xu, B.; Guo, W.; Han, L.Q.; Yao, A.Y.; Ge, Z.M.; Li, R.T.; Cui, J.R. J. Chin. Pharm. Sci.2012, 21, 448-458.

[5] Chen, D.; Frezza, M.; Schmitt, S.; Kanwar, J.; Dou, Q.P. Curr. Cancer Drug Tar. 2011, 11, 239-253.

[6] Korolchuk, V.I.; Menzies, F.M.; Rubinsztein, D.C. FEBS Lett. 2010, 584, 1393-1398.

[7] Klionsky, D.J. Autophagy. 2012, 8, 445-544.

[8] Backues, S.K.; Chen, D.C.; Ruan, J.S.; Xie, Z.P.; Klionsky, D.J. Autophagy. 2013, 10, 155-164.

[9] Miller-Fleming, L.; Cheong, H.; Antas, P.; Klionsky, D.J. Autophagy. 2014, 10, 514-517.

[10] Samul, T.P.; Anil, S. J. Clin. Cell Immunol. 2012, S5, 1-6.

[11] Maria, H.H.; Marja, J. Autophagy. 2008, 4, 574-580.

[12] Milani, M.; Rzymski, T.; Mellor, H.R.; Pike, L.; Bottini, A.; Generali, D.; Harris, A.L. Cancer Res. 2009, 69, 4415-4423.

[13] Bruning, A.; Martina, R.; Friese, K. Mol. Oncol. 2013, 7, 1012-1018.

[14] Feng, Z.H.; Levine, A.J. Trends Cell Biol. 2010, 20, 427-434.

[15] Kim, J.; Kundu, M.; Viollet, B.; Guan, K.L. Nat. Cell Biol. 2011, 13, 132-141.

[16] Rabinowitz, J.D.; White, E. Science. 2010, 330,1344-1348.

[17] Takahashi, Y.; Coppola, D.; Matsushita, N.; Cualing, H.D.; Sun, M.; Sato, Y.; Liang, C.Y.; Jung, J.U.; Cheng, J.Q.; Mule, J.J.; Pledger, J.; Wang, H.G. Nat. Cell Biol. 2007, 9, 1142-1151.

[18] Miracco, C.; Cosci, E.; Oliveri, G.; Pacenti, L.; Monciatti, I.; Mannucci, S.; Nisi, M.C.D.; Toscano, M.; Malagnino, V.; Falzarano, S.M.; Pirtioli, L.; Tosi, P. Int. J. Oncol. 2007, 30, 429-436.

[19] Kang, M.R.; Kim, M.S.; Oh, J.E.; Kim, Y.R.; Song, S.Y.; Kim, S.S.; Ahn, C.H.; Yoo, N.J.; Lee, S.H. J. Pathol. 2009, 217, 702-706.

[20] Zhu, K.; Dunner, K.; McConkey, D.J. Oncogene. 2010, 29, 451-462.

[21] Wu, Z.J.; Chang, P.C.; Yang, J.C.; Chu, C.Y.; Wang, L.Y.; Chen, N.T.; Ma, A.H.; Desai, S.J.; Lo, S.H.; Evans, C.P.; Lam, K.S.; Kung, H.J. Gene Cancer. 2010, 1, 40-49.

新型蛋白酶体抑制剂YSY-01A诱导PC-3M细胞自噬的作用

A new proteasome inhibitor YSY-01A induced autophagy in PC-3M cells

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 11

编辑推荐

Metrics

本文评价

[1]	郑吴殷晓, 李海平, 罗来春, 胡春玲, 尤朋涛. TOPC通过抑制PI3K/AKT/mTOR通路, 抑制miR-210, Atg7诱导H1975细胞凋亡[J]. 中国药学(英文版), 2023, 32(11): 881-892.
[2]	张精亮, 胡涛, 刘晓岩, 朱元军, 陈晓玲, 刘晔, 王银叶. 002C-3通过抑制MMPs和细胞自噬并激活细胞存活相关的钙信号通路保护小鼠脑缺血再灌注损伤[J]. 中国药学(英文版), 2016, 25(8): 598-604.
[3]	姚书扬, 周玥. 二肽乙烯磺胺类似物作为蛋白酶体抑制剂的研究[J]. 中国药学(英文版), 2016, 25(6): 408-418.
[4]	赵曜, 张婧莹, 胡英杰, 吴佳栓, 卜英子, 吕万良. 柔红霉素与罗非昔布联合应用增强三阴性乳腺癌的治疗效应与作用机制[J]. 中国药学(英文版), 2016, 25(6): 438-447.
[5]	孙婷, 袁霞, 黄薇, 郭维, 葛泽梅, 李润涛, 崔景荣. 蛋白酶体抑制剂YSY01-A对非小细胞肺癌的作用机制及其与顺铂联用作用的研究[J]. 中国药学(英文版), 2015, 24(9): 607-616.
[6]	陈溢欣, 袁霞, 葛泽梅, 冉福香, 吴军, 李润涛, 崔景荣. 新型蛋白酶体抑制剂YSY-01A对人胃癌MGC-803的作用及相关蛋白研究[J]. 中国药学(英文版), 2014, 23(9): 601-609.
[7]	杨冠宇, 孙琦, 王超, 梁磊, 许凤荣, 牛彦, 徐萍. 磺胺类黄酮衍生物20S蛋白酶体抑制剂的设计、合成与活性评价[J]. 中国药学(英文版), 2014, 23(9): 626-630.
[8]	贾璇, 袁霞, 楚明明, 冉福香, 李润涛^, 崔景荣^. 新的蛋白酶体抑制剂YSY-01A对SK-OV-3细胞的周期阻滞作用[J]. 中国药学(英文版), 2013, 22(6): 483-490.
[9]	佟侃, 刘敬弢, 袁霞, 徐波, 郭维, 韩利强, 姚书扬, 葛泽梅, 李润涛^, 崔景荣^. 新的蛋白酶体抑制剂YSY-01A对HT-29细胞的周期阻滞作用[J]. , 2012, 21(5): 448-458.
[10]	韩利强, 张寓安, 姚书扬, 徐波, 葛泽梅, 崔景荣, 李润涛^*. 肽醛类前药衍生物作为蛋白酶体抑制剂的研究[J]. , 2012, 21(1): 21-27.
[11]	付刚, 邹晓民, 傅翌秋, 牟科, 马超, 吕扬, 徐萍^*. 保护的氨烷基化亚磺酰双内酯的合成[J]. , 2007, 16(2): 119-124.