Mst1 overexpression inhibited the growth of human non-small cell lung cancer in vitro and in vivo.
Mammalian STE20-like kinase 1 (Mst1) ubiquitously encodes serine threonine kinase, which is a 59-kDa class II GC kinase that shares 76% identity in amino-acid sequence with MST2, and is the closest mammalian homolog of Drosophila Hippo protein kinase, a major inhibitor of cell proliferation in Drosophila. Recent studies have shown that Mst1 and Mst2 perform tumor-suppressor function in a redundant manner and were originally identified as pro-apoptotic cytoplasmic kinases important for controlling cell growth, proliferation, apoptosis and organ size. We used recombinant eukaryotic expression vector containing human wild-type Mst1 gene to transfect human non-small cell lung cancer (NSCLC) A549 cells in vitro and in vivo. The results showed that Mst1 overexpression inhibited cell proliferation and induced apoptosis of A549 cells, promoted Yes-associated protein (YAP) (Ser127) phosphorylation and downregulated the transcriptional level of Cystein-rich protein connective tissue growth factor (CTGF), amphiregulin (AREG) and Survivin. In human NSCLC-cell-A549-xenograft models, Mst1 gene or cisplatin alone suppressed the growth of tumors and increased the cytoplasm-positive expression levels of YAP and Phospho-YAP (Ser127) proteins; however, their combination had the strongest anticancer effects. Overall, Mst1 has an important role in inhibiting the growth of NSCLC in vitro and in vivo; its antiproliferative effect is associated with induction of apoptosis through promotion of the cytoplasmic localization and phosphorylation of YAP protein at Ser127 site, indicating that Mst1 may be developed as a promising therapeutic target for NSCLC.
Department of Biochemistry and Molecular Biology, Basic Medical College of Nanchang University, Nanchang, China.
C M
CM
Xu
W W
WW
Liu
C J
CJ
Liu
C
C
Wen
H F
HF
Lu
F S
FS
Wan
D000595:Amino Acid Sequence; D066258:Amphiregulin; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis / Q000235:genetics; D066255:EGF Family of Proteins; D005260:Female; D018014:Gene Transfer Techniques; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D064593:Heterografts; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D000077022:Survivin; D014162:Transfection; D000099317:Hippo Kinases
D066258:Amphiregulin; D055513:Connective Tissue Growth Factor; D066255:EGF Family of Proteins; D006023:Glycoproteins; D051034:Inhibitor of Apoptosis Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D000077022:Survivin; C587848:AREG protein, human; C587849:Areg protein, mouse; C107489:BIRC5 protein, human; C526317:CCN2 protein, human; C095566:STK4 protein, human; D000099317:Hippo Kinases