title: Mitotic cell death caused by follistatin-like 1 inhibition is associated with up-regulated Bim by inactivated Erk1/2 in human lung cancer cells.
abstract: 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.
authors.affiliation: Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Korea.
authors.forename: Kieun
authors.initials: K
authors.lastname: Bae
authors.affiliation: Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Korea.
authors.forename: Kyoung Eun
authors.initials: KE
authors.lastname: Park
authors.affiliation: Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: Han
authors.affiliation: Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Korea.
authors.forename: Jongkwang
authors.initials: J
authors.lastname: Kim
authors.affiliation: Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Korea.
authors.forename: Kyungtae
authors.initials: K
authors.lastname: Kim
authors.affiliation: Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Korea.|College of Veterinary Medicine, Konkuk University, Gwangjin-gu, Seoul, Korea.
authors.forename: Kyong-Ah
authors.initials: KA
authors.lastname: Yoon
mesh_terms: D000072283:A549 Cells; D017209:Apoptosis / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11 / Q000096:biosynthesis*; D016203:CDC2 Protein Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D056744:Cyclin B1 / Q000737:chemistry; D018844:Cyclin-Dependent Kinases / Q000737:chemistry; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D038702:Follistatin-Related Proteins / Q000235:genetics* / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics; D008938:Mitosis / Q000235:genetics; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D000072224:Bcl-2-Like Protein 11; C534699:CCNB1 protein, human; D056744:Cyclin B1; D038702:Follistatin-Related Proteins; D006657:Histones; D034741:RNA, Small Interfering; C448799:FSTL1 protein, human; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D053453:Caspase 9
keywords: Bim; Erk1/2; FSTL1; apoptosis; lung cancer