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.

FSTL1 Promotes Metastasis and Chemoresistance in Esophageal Squamous Cell Carcinoma through NFκB–BMP Signaling Cross-talk

“…FSTL1 has previously been reported to play both oncogenic and tumor-suppressive roles in various cancer types (23)(24)(25)(26)(27)(28)(29)(30). Yet, to the best of our knowledge, this is the first study to report its significance in ESCC.…”

“…However, FSTL1 was found to be overexpressed in astrocytic brain tumors (27) and also to enhance the metastasis of cancer cells in breast, prostate, skin, and pancreatic cancers (28)(29). A recent study have also found knockdown of FSTL1 to induce mitotic cell death and BIM upregulation in nonsmall cell lung carcinoma cells (30). However, to date, the clinical significance and functional role of endogenous and secretory FSTL1 and the molecular mechanism by which it drives ESCC pathogenesis has not been reported.…”

Many si/shRNAs can kill cancer cells by targeting multiple survival genes through an off-target mechanism

“…3) FSTL1 (follistatin-like 1) is a putative activin-binding protein. Knockdown of FSTL1 in lung cancer cells resulted in mitotic arrest followed by apoptosis promoted by the activation of caspase-3 and -9 (Bae et al, 2016). FSTL1 is downregulated during cellular senescence of human mesenchymal stem cells (Yoo, Choi, & Kim, 2013).…”

Effects of FSTL1 on the proliferation and motility of breast cancer cells and vascular endothelial cells

“…An increasing number of studies have indicated that the secreted protein FSTL1 plays key roles in cardiovascular diseases and might be involved in the pathogenesis of cancer . However, it is not clear whether FSTL1 is involved in breast cancer development and progression.…”

“…An increasing number of studies have indicated that the secreted protein FSTL1 plays key roles in cardiovascular diseases and might be involved in the pathogenesis of cancer. [22][23][24][25] However, it is not clear whether FSTL1 is involved in breast cancer development and progression. Excessive proliferation plays a critical role in tumor growth; therefore, in this study we tested the effects of FSTL1 on proliferation of BT-549 breast cancer cells.…”