RESUMO
The processes that lead to lung adenocarcinoma (LUAD) metastasis are poorly characterized. Spindle and kinetochore associated complex subunit 3 (SKA3) plays a key role in cervical cancer development, but its contribution to LUAD is unknown. Here, we found that SKA3 is overexpressed in LUAD and its expression correlates with lymph node metastasis and poor prognosis. SKA3 silencing experiments identified SKA3 as an oncogene that promotes the metastasis of LUAD cell lines and tissues. SKA3 was found to induce the expression of matrix metalloproteinase (MMP)-2, -7, and -9, which activate PI3K-AKT. SKA3 was also found to bind and activate EGFR to activate PI3K-AKT. In summary, we identify a role for SKA3 in LUAD metastasis through its ability to bind EFGR and activate PI3K-AKT signaling.
Assuntos
Adenocarcinoma de Pulmão/enzimologia , Proteínas de Ciclo Celular/metabolismo , Movimento Celular , Neoplasias Pulmonares/enzimologia , Proteínas Associadas aos Microtúbulos/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/secundário , Animais , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 7 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Nus , Proteínas Associadas aos Microtúbulos/genética , Transdução de SinaisRESUMO
BACKGROUND: Whether the c-Jun N-terminal kinase (JNK) pathway mediates apoptosis in sepsis-induced acute lung injury is not known. Here we investigated the effect of JNK inhibition in a rat model of sepsis-induced lung injury, and assessed expression of JNK and endoplasmic reticulum stress-related proteins. METHODS: Sepsis was established by cecal ligation and puncture (CLP) in 48 male Sprague-Dawley rats. 32 additional rats underwent sham surgery. 24 CLP rats and 24 sham rats received tail vein injection of 30 mg/kg SP600125. The rest received saline injection. At 6, 12 and 24 h after surgery, blood, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. p-JNK, XBP-1, ATF-4 and CHOP levels of the lung tissue were measured by western blot; and the JNK mRNA levels were measured by qPCR. RESULTS: The W/D ratios of lungs in the CLP group were significantly higher than those in the sham group, but lower those in the CLP+JNK inhibitor group (P<0.05). TUNEL staining revealed significantly more apoptotic cells in the lungs of the CLP group than the sham group, and in the CLP+JNK inhibitor group the apoptotic index was significantly reduced (P<0.05). XBP-1, ATF-4, CHOP and p-JNK protein levels and JNK mRNA levels were significantly elevated in the CLP group (P<0.05), but significantly ameliorated in the CLP+JNK inhibitor group (P<0.05). CONCLUSIONS: Inhibition of the JNK signaling pathway mitigates sepsis-induced lung injury. Our results suggest that JNK signaling promotes endoplasmic reticulum stress and thus apoptosis in sepsis-induced lung injury.
RESUMO
Sunitinib, which is a multitargeted tyrosine-kinase inhibitor, exhibits antiangiogenic and antitumor activity, and extends survival of patients with metastatic renal-cell carcinoma (mRCC) and gastrointestinal stromal tumors (GIST). This molecule has also been reported to be associated with cardiotoxicity at a high frequency, but the mechanism is still unknown. In the present study, we observed that Sunitinib showed high anti-proliferative effect on H9c2 cardiac muscle cells measured by PI staining and the MTT assay. But apoptotic markers (PARP cleavage, caspase 3 cleavage and chromatin condensation) were uniformly negative in H9c2 cells after Sunitinib treatment for 48 h, indicating that another cell death pathway may be involved in Sunitinib-induced cardiotoxicity. Here we found Sunitinib dramatically increased autophagic flux in H9c2 cells. Acidic vesicle fluorescence and high expression of LC3-II in H9c2 cells identified autophagy as a Sunitinib-induced process that might be associated with cytotoxicity. Furthermore, knocking down Beclin 1 by RNA-interference to block autophagy in H9c2 cells revealed that the death rate was decreased when treated with Sunitinib in comparison to control cells. These results confirmed that autophagy plays an important role in Sunitinib-mediated H9c2 cells cytotoxicity. Taken together, the data presented here strongly suggest that autophagy is associated with Sunitinib-induced cardiotoxicity, and that inhibition of autophagy constitutes a viable strategy for reducing Sunitinib-induced cardiomyocyte death thereby alleviating Sunitinib cardiotoxicity.