A heterodimer of α and β hemoglobin chains functions as an innate anticancer agent
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ABSTRACT:
PROVIDER: PRJNA935740 | ENA |
REPOSITORIES: ENA
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Project description:Metastatic (as well as tumor) microenvironments contain both cancer-promoting as well as cancer restraining factors. The balance between these opposing forces determines the fate of cancer cells that disseminate to secondary organ sites. In search for microenvironmental drivers or inhibitors of metastasis, we identified, in a previous study, the beta subunit of hemoglobin (HBB) as a lung-derived antimetastatic factor. In the present study, exploring mechanisms leading to melanoma brain metastasis, we discovered that brain-derived factors restrain proliferation and induce apoptosis and necrosis of brain-metastasizing melanoma cells. Employing various purification procedures, we identified a heterodimer composed of hemoglobin alpha and beta chains that performs these anti-metastatic functions. Neither the alpha nor the beta subunit alone were inhibitory. An alpha/beta chain dimer chemically purified from human hemoglobin inhibited the cell viability of primary melanomas, melanoma brain metastasis (MBM), and breast cancer cell lines. The dimer-induced DNA damage, cell cycle arrest at the SubG1 phase, apoptosis, and significant necrosis in four MBM cell lines. Proteomic analysis of dimer-treated MBM cells revealed that the dimer downregulates the expression of BRD4, GAB2, and IRS2 proteins playing crucial roles in cancer cell sustainability and progression.
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Project description:Innate factors such as β-defensins may exhibit anti-cancer functions, serving as a first line of defense against incipient or dormant cancer cells. In previous studies, our lab demonstrated that hemoglobin-derived factors such as the hemoglobin beta chain or an alpha/beta heterodimer of hemoglobin trigger apoptosis and necrosis in neuroblastoma and brain-metastasizing melanoma cells, respectively. In addition to its cytotoxic function, the alpha/beta hemoglobin dimer downregulated the expression of proteins such as BRD4 and IRS2, which perform essential functions in tumorigenesis and cancer progression. In the present study, we proved the concept, raised for the first time in this study, that in addition to their anti-cancer functions, innate resistance factors could serve as pathfinders to identify theranostic targets on progressing cancer cells.
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Project description:A heterodimer of hemoglobin identifies theranostic targets on brain-metastasizing melanoma cells
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Project description:BACKGROUND & AIMS: Recent studies revealed that hemoglobin is expressed in some non-erythrocytes and it suppresses oxidative stress when overexpressed. Oxidative stress plays a critical role in the pathogenesis of non-alcoholic steatohepatitis (NASH). This study was to investigate whether hemoglobin is expressed in hepatocytes and how it is related to oxidative stress in NASH patients. METHODS: Microarray was performed to identify differentially expressed genes in NASH. Quantitative real time PCR (qRT-PCR) was used to examine gene expression levels. Western blotting and immunofluorescence staining were employed to examine hemoglobin proteins. Flow cytometry was used to measure intracellular oxidative stress. RESULTS: Analysis of microarray gene expression data has revealed a significant increase in the expression of hemoglobin alpha (HBA1) and beta (HBB) in liver biopspies from NASH patients. Increased hemoglobin expression in NASH was validated by qRT-PCR. However, the expression of erythrocyte specific marker genes such as SPTA, SPTB, GYPA, GATA1, and ALAS2 did not change, indicating that increased hemoglobin expression in NASH was not from erythropoiesis, but could result from increased expression in hepatocytes. Immunofluorescence staining demonstrated positive HBA1 and HBB expression in the hepatocytes of NASH livers. Hemoglobin expression was also observed in human hepatocellular carcinoma HepG2 cell line. Furthermore, treatment with hydrogen peroxide, a known oxidative stress inducer, induced a dose dependent increase in HBA1 expression in HepG2 cells. Intriguingly, forced hemoglobin expression suppressed oxidative stress. CONCLUSIONS: Oxidative stress upregulates hemoglobin expression in hepatocytes. Suppression of oxidative stress by hemoglobin could be a mechanism to protect hepatocytes from oxidative damage. These findings suggest that hemoglobin is an inducible antioxidant in hepatocytes in response to increased oxidative stress as found in NASH livers. Twelve biopsy diagnosed NASH patients were included in this study. For control groups, total RNA from 5 different subjects were purchased from ADMET. These subjects are free from liver disease.
2010-10-20 | E-GEOD-24807 | biostudies-arrayexpress
Project description:Transcriptional profiling was conducted on RNA from 16 prostatic cancer cell lines to identify genes whose expression level correlate with sensitivity of an anti-tumor agent (dasatinib). Keywords: comparison of sensitive group versus resistant group of cell lines to agent
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Project description:BACKGROUND & AIMS: Recent studies revealed that hemoglobin is expressed in some non-erythrocytes and it suppresses oxidative stress when overexpressed. Oxidative stress plays a critical role in the pathogenesis of non-alcoholic steatohepatitis (NASH). This study was to investigate whether hemoglobin is expressed in hepatocytes and how it is related to oxidative stress in NASH patients. METHODS: Microarray was performed to identify differentially expressed genes in NASH. Quantitative real time PCR (qRT-PCR) was used to examine gene expression levels. Western blotting and immunofluorescence staining were employed to examine hemoglobin proteins. Flow cytometry was used to measure intracellular oxidative stress. RESULTS: Analysis of microarray gene expression data has revealed a significant increase in the expression of hemoglobin alpha (HBA1) and beta (HBB) in liver biopspies from NASH patients. Increased hemoglobin expression in NASH was validated by qRT-PCR. However, the expression of erythrocyte specific marker genes such as SPTA, SPTB, GYPA, GATA1, and ALAS2 did not change, indicating that increased hemoglobin expression in NASH was not from erythropoiesis, but could result from increased expression in hepatocytes. Immunofluorescence staining demonstrated positive HBA1 and HBB expression in the hepatocytes of NASH livers. Hemoglobin expression was also observed in human hepatocellular carcinoma HepG2 cell line. Furthermore, treatment with hydrogen peroxide, a known oxidative stress inducer, induced a dose dependent increase in HBA1 expression in HepG2 cells. Intriguingly, forced hemoglobin expression suppressed oxidative stress. CONCLUSIONS: Oxidative stress upregulates hemoglobin expression in hepatocytes. Suppression of oxidative stress by hemoglobin could be a mechanism to protect hepatocytes from oxidative damage. These findings suggest that hemoglobin is an inducible antioxidant in hepatocytes in response to increased oxidative stress as found in NASH livers.
2010-10-21 | GSE24807 | GEO
Project description:Platinum-based metallodrugs are the most widely used anticancer agents. Their reduced effectiveness after repeat dosing (resistance) constitutes a major clinical problem. In this experiment we study a potent organo-osmium compound with improved activity over cisplatin and no cross-resistance in platinum-resistant cancers. A2780 cells were exposed to an osmium anticancer compound and to a negative control solution, in triplicate. At 0, 4, 12, 24 and 48 h, cells were collected for each condition, and whole cell RNA was extracted. Samples were purified and QC checked before Truseq library preparation and Illumina sequencing. Each sample had approximately 30 million paired-end reads. Samples were mapped to the human genome using Tophat2 and differential expression analysed using edgeR.
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