Mitotic cell death caused by follistatin-like 1 inhibition is associated with up-regulated Bim by inactivated Erk1/2 in human lung cancer cells

被引:30
作者
Bae, Kieun [1 ]
Park, Kyoung Eun [1 ]
Han, Jihye [1 ]
Kim, Jongkwang [1 ]
Kim, Kyungtae [1 ]
Yoon, Kyong-Ah [1 ,2 ]
机构
[1] Natl Canc Ctr, Res Inst & Hosp, Goyang, Gyeonggi, South Korea
[2] Konkuk Univ, Coll Vet Med, Seoul 05029, South Korea
基金
新加坡国家研究基金会;
关键词
FSTL1; lung cancer; apoptosis; Bim; Erk1/2; C-JUN; INDUCED APOPTOSIS; MULTIPLE-MYELOMA; LEUKEMIA-CELLS; MCL-1; PHOSPHORYLATION; ARREST; CLEAVAGE; DEGRADATION; METASTASIS;
D O I
10.18632/oncotarget.6729
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Follistatin-like 1 (FSTL1) was identified as a novel pro-inflammatory protein showing high-level expression in rheumatoid arthritis. The protective effect of FSTL1 via the inhibition of apoptosis was reported in myocardial injury. However, the functional mechanism of FSTL1 in cancer is poorly characterized, and its proliferative effects are ambiguous. Here, we examined the effects of FSTL1 on cellular proliferation and cell cycle checkpoints in lung cancer cells. FSTL1 inhibition induced the cellular portion of G2/M phase in human lung cancer cells via the accumulation of regulators of the transition through the G2/M phase, including the cyclin-dependent kinase 1 (Cdk1)-cyclin B1 complex. An increase in histone H3 phosphorylation (at Ser10), another hallmark of mitosis, indicated that the knockdown of FSTL1 in lung cancer cells stimulated a mitotic arrest. After that, apoptosis was promoted by the activation of caspase-3 and -9. Protein level of Bim, a BH3 domain-only, pro-apoptotic member and its isoforms, BimL, BimS, and BimEL were up-regulated by FSTL1 inhibition. Degradation of Bim was blocked in FSTL1-knockdown cells by decreased phosphorylation of Bim. Increased BimEL as well as decreased phosphorylated Erk1/2 is essential for cell death by FSTL1 inhibition in NCI-H460 cells. Taken together, our results suggest that the knockdown of FSTL1 induces apoptosis through a mitotic arrest and caspase-dependent cell death. FSTL1 plays the important roles in cellular proliferation and apoptosis in lung cancer cells, and thus can be a new target for lung cancer treatment.
引用
收藏
页码:18076 / 18084
页数:9
相关论文
共 27 条
[1]   The Noxa/Mcl-1 axis regulates susceptibility to apoptosis under glucose limitation in dividing T cells [J].
Alves, Nuno L. ;
Derks, Ingrid A. M. ;
Berk, Erik ;
Spijker, Rene ;
van Lier, Rene A. W. ;
Eldering, Eric .
IMMUNITY, 2006, 24 (06) :703-716
[2]   Tumor suppressor effect of follistatin-like 1 in ovarian and endometrial carcinogenesis-025EFa differential expression and functional analysis [J].
Chan, Queeny K. Y. ;
Ngan, Hextan Y. S. ;
Ip, Philip P. C. ;
Liu, Vincent W. S. ;
Xue, W. C. ;
Cheung, Annie N. Y. .
CARCINOGENESIS, 2009, 30 (01) :114-121
[3]   Cdk1/cyclin B plays a key role in mitotic arrest-induced apoptosis by phosphorylation of Mcl-1, promoting its degradation and freeing Bak from sequestration [J].
Chu, Rong ;
Terrano, David T. ;
Chambers, Timothy C. .
BIOCHEMICAL PHARMACOLOGY, 2012, 83 (02) :199-206
[4]   Targeting Mcl-1 for multiple myeloma (MM) therapy: Drug-induced generation of Mcl-1 fragment Mcl-1128-350 triggers MM cell death via c-Jun upregulation [J].
Fan, Fengjuan ;
Tonon, Giovanni ;
Bashari, Muhammad Hasan ;
Vallet, Sonia ;
Antonini, Elena ;
Goldschmidt, Hartmut ;
Schulze-Bergkamen, Henning ;
Opferman, Joseph T. ;
Sattler, Martin ;
Anderson, Kenneth C. ;
Jaeger, Dirk ;
Podar, Klaus .
CANCER LETTERS, 2014, 343 (02) :286-294
[5]   Nucleolar AATF regulates c-Jun-mediated apoptosis [J].
Ferraris, Saima E. ;
Isoniemi, Kimmo ;
Torvaldson, Elin ;
Anckar, Julius ;
Westermarck, Jukka ;
Eriksson, John E. .
MOLECULAR BIOLOGY OF THE CELL, 2012, 23 (21) :4323-4332
[6]   Follistatin-like 1 (Fstl1) is a bone morphogenetic protein (BMP) 4 signaling antagonist in controlling mouse lung development [J].
Geng, Yan ;
Dong, Yingying ;
Yu, Mingyan ;
Zhang, Long ;
Yan, Xiaohua ;
Sun, Jingxia ;
Qiao, Long ;
Geng, Huixia ;
Nakajima, Masahiro ;
Furuichi, Tatsuya ;
Ikegawa, Shiro ;
Gao, Xiang ;
Chen, Ye-Guang ;
Jiang, Dianhua ;
Ning, Wen .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (17) :7058-7063
[7]   Noxa up-regulation and Mcl-1 cleavage are associated to apoptosis induction by bortezomib in multiple myeloma [J].
Gomez-Bougie, Patricia ;
Wuilleme-Toumi, Soraya ;
Menoret, Emmanuelle ;
Trichet, Valerie ;
Robillard, Nelly ;
Philippe, Moreau ;
Bataille, Regis ;
Amiot, Martine .
CANCER RESEARCH, 2007, 67 (11) :5418-5424
[8]   Phosphorylation of Mcl-1 by CDK1-cyclin B1 initiates its Cdc20-dependent destruction during mitotic arrest [J].
Harley, Margaret E. ;
Allan, Lindsey A. ;
Sanderson, Helen S. ;
Clarke, Paul R. .
EMBO JOURNAL, 2010, 29 (14) :2407-2420
[9]   Glucocorticoid-mediated BIM induction and apoptosis are regulated by Runx2 and c-Jun in leukemia cells [J].
Heidari, N. ;
Miller, A. V. ;
Hicks, M. A. ;
Marking, C. B. ;
Harada, H. .
CELL DEATH & DISEASE, 2012, 3 :e349-e349
[10]   Cleavage of Mcl-1 by caspases impaired its ability to counteract Bim-induced apoptosis [J].
Herrant, M ;
Jacquel, A ;
Marchetti, S ;
Belhacène, N ;
Colosetti, P ;
Luciano, F ;
Auberger, P .
ONCOGENE, 2004, 23 (47) :7863-7873