Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sorafenib (Nexavar) is a broad-spectrum multikinase inhibitor that proves effective in treating advanced renal-cell carcinoma and liver cancer. Despite its well-characterized mechanism of action on several established cancer-related protein kinases, sorafenib causes variable responses among human tumors, although the cause for this variation is unknown. In an unbiased screening of an oncology drug library, we found that sorafenib activates recruitment of the ubiquitin E3 ligase Parkin to damaged mitochondria. We show that sorafenib inhibits the activity of both complex II/III of the electron transport chain and ATP synthase. Dual inhibition of these complexes, but not inhibition of each individual complex, stabilizes the serine-threonine protein kinase PINK1 on the mitochondrial outer membrane and activates Parkin. Unlike the protonophore carbonyl cyanide m-chlorophenylhydrazone, which activates the mitophagy response, sorafenib treatment triggers PINK1/Parkin-dependent cellular apoptosis, which is attenuated upon Bcl-2 overexpression. In summary, our results reveal a new mechanism of action for sorafenib as a mitocan and suggest that high Parkin activity levels could make tumor cells more sensitive to sorafenib's actions, providing one possible explanation why Parkin may be a tumor suppressor gene. These insights could be useful in developing new rationally designed combination therapies with sorafenib.
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PMID:Sorafenib targets the mitochondrial electron transport chain complexes and ATP synthase to activate the PINK1-Parkin pathway and modulate cellular drug response. 2867 64

Autophagy is required for benign hepatic tumors to progress into malignant hepatocellular carcinoma. However, the mechanism is unclear. Here, we report that mitophagy, the selective removal of mitochondria by autophagy, positively regulates hepatic cancer stem cells (CSCs) by suppressing the tumor suppressor p53. When mitophagy is enhanced, p53 co-localizes with mitochondria and is removed by a mitophagy-dependent manner. However, when mitophagy is inhibited, p53 is phosphorylated at serine-392 by PINK1, a kinase associated with mitophagy, on mitochondria and translocated into the nucleus, where it binds to the NANOG promoter to prevent OCT4 and SOX2 transcription factors from activating the expression of NANOG, a transcription factor critical for maintaining the stemness and the self-renewal ability of CSCs, resulting in the reduction of hepatic CSC populations. These results demonstrate that mitophagy controls the activities of p53 to maintain hepatic CSCs and provide an explanation as to why autophagy is required to promote hepatocarcinogenesis.
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PMID:Mitophagy Controls the Activities of Tumor Suppressor p53 to Regulate Hepatic Cancer Stem Cells. 3122 43

Matrine is a natural alkaloid isolated from the root and stem of the legume plant Sophora. Its anti-proliferative and pro-apoptotic effects on several types of cancer have been well-documented. However, the role of matrine in regulating mitochondrial homeostasis, particularly mitophagy in liver cancer apoptosis, remains uncertain. The aim of our study was to explore whether matrine promotes liver cancer cell apoptosis by modifying mitophagy. HepG2 cells were used in the study and treated with different doses of matrine. Cell viability and apoptosis were determined by MTT assay, TUNEL staining, western blotting, and LDH release assay. Mitophagy was monitored by immunofluorescence assay and western blotting. Mitochondrial function was assessed by immunofluorescence assay, ELISA, and western blotting. The results of our study indicated that matrine treatment dose-dependently reduced cell viability and increased the apoptotic rate of HepG2 cells. Functional studies demonstrated that matrine treatment induced mitochondrial dysfunction and activated mitochondrial apoptosis by inhibiting protective mitophagy. Re-activation of mitophagy abolished the pro-apoptotic effects of matrine on HepG2 cells. Molecular investigations further confirmed that matrine regulated mitophagy via the PINK1/Parkin pathways. Matrine blocked the PINK1/Parkin pathways and repressed mitophagy, whereas activation of the PINK1/Parkin pathways increased mitophagy activity and promoted HepG2 cell survival in the presence of matrine. Together, our data indicated that matrine promoted HepG2 cell apoptosis through a novel mechanism that acted via inhibiting mitophagy and the PINK1/Parkin pathways. This finding provides new insight into the molecular mechanism of matrine for treating liver cancer and offers a potential target to repress liver cancer progression by modulating mitophagy and the PINK1/Parkin pathways.
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PMID:Matrine promotes liver cancer cell apoptosis by inhibiting mitophagy and PINK1/Parkin pathways. 3020 83

Alantolactone (Ala), a major sesquiterpene lactone extracted from Inula helenium, exerts potent anti-tumour activities in various cancers. However, the underlying mechanism of such activities is still ambiguous. This study focused on evaluating the anti-tumour effects and molecular mechanisms of Ala on HepG2 cells. Our results demonstrated that Ala might inhibit cellular proliferation, induce G2/M phase arrest and apoptosis in HepG2 cells. Specifically, this study confirmed that Ala induced G2/M phase arrest by upregulating p21, downregulating cyclin A1 and cyclin B1, and promoting cellular apoptosis by increasing the expression of cleaved caspase-3 and PARP. Furthermore, Ala caused an increase in reactive oxygen species (ROS) level and inhibition of ROS production significantly prevented Ala-induced apoptosis. Interestingly, the accumulation of ROS, in turn, suppressed the downstream AKT signalling. Finally, mitophagy of Ala-treated HepG2 cells was observed by Mito/Lyso staining. Mitophagy was significantly inhibited by downregulation of the expression of PINK1 and Parkin proteins. The inhibition of mitophagy by a mitophagy inhibitor was found to markedly enhance Ala-mediated apoptosis and growth inhibition in HepG2 cells. Consequently, Ala induced cellular apoptosis via ROS-mediated suppression of AKT signalling and inhibition of PINK1-mediated mitophagy. Thus, Ala has potential to be used for the treatment of liver cancer.
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PMID:Alantolactone induces apoptosis through ROS-mediated AKT pathway and inhibition of PINK1-mediated mitophagy in human HepG2 cells. 3111 36

Mitochondrial transcription termination factor 3 (MTERF3) is a negative regulator of mitochondrial transcription. MTERF3 is overexpressed in liver cancer, pancreatic cancer, lung cancer, and breast cancer. However, whether MTERF3 is up-regulated in brain glioma is still unclear. The aim of this study was to investigate the expression and clinicopathological significance of MTERF3 in brain glioma and to analyze its potential prognostic value in brain glioma. Immunohistochemistry, Western blot, and a semi-quantitative RT-PCR were performed to analyze the protein and mRNA expression levels of MTERF3 in 28 human brain glioma tissues and 10 noncancerous brain tissues. The expression data of MTERF3 and its clinical information in brain glioma were downloaded from the TCGA dataset using R 2.15.3 software. The relationship between the expression of MTERF3 and its clinicopathological characteristics and its prognostic value was analyzed. A Cox regression model was used for a multivariate analysis of the factors affecting the prognosis of brain glioma. The immunohistochemistry results showed that the MTERF3 protein is located in the cytoplasm, and the positive expression rate of the MTERF3 protein in brain glioma tissues is 64.29%. We found that the positive expression rate of the MTERF3 protein in high-grade glioma tissues (81.25%) is higher than it is in low-grade glioma tissues (41.67%). The expression levels of the MTERF3 mRNA and protein in brain glioma tissues are significantly higher than they are in the noncancerous brain tissues. Moreover, the expression of MTERF3 is significantly correlated with age, tumor type, and pathological classification (P<0.05). A Kaplan-Meier analysis showed that a high expression level of MTERF3 mRNA indicated a poor prognosis (log rank P<0.01). Furthermore, a multivariate Cox regression analysis showed that age and tumor type were independent prognostic factors for brain glioma patients. A GEPIA analysis suggested that the expression levels of MTERF3 are positively correlated with the TFAM, TFB1M, TFB2M, MTERF1, MTERF2, TEFM, and MFN1 genes, but negatively correlated with the PINK1 gene. The expression level of MTERF3 had no correlation with the MTERF4 gene. In conclusion, these data indicate that the expression of MTERF3 in glioma tissue samples can be used as a prognostic factor for patients with glioma and that a high MTERF3 expression correlates with a poor prognosis in glioma patients.
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PMID:A high expression of MTERF3 correlates with tumor progression and predicts poor outcomes in patients with brain glioma. 3193 14