TRIM28 attenuates Bortezomib sensitivity of hepatocellular carcinoma cells through enhanced proteasome expression.
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ABSTRACT:
SUBMITTER: Zhang J
PROVIDER: S-EPMC8782260 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hepatocellular carcinoma (HCC) represents a common malignancy, and mechanisms of acquired sorafenib resistance during the treatment of HCC patients remain elusive. The present study performed integrated bioinformatics analysis and explored the potential action of heme oxygenase 1 (HMOX1) in sorafenib-resistant HCC cells. Differentially expressed genes (DEGs) of the sorafenib-resistant group as compared to the sorafenib-sensitive group from GSE140202 and GSE143233 were extracted. Fifty common DEGs between GSE140202 and GSE143233 were extracted. Ten hub genes were identified from the protein-protein interaction network based on common DEGs. Experimental results revealed the upregulation of HMOX1 in sorafenib-resistant HCC cells. HMOX1 silence promoted the sensitivity to sorafenib in sorafenib-resistant HCC cells; overexpression of HMOX1 attenuated the sensitivity. In addition, HMOX1 silence downregulated the mRNA expression of ABC transporters in sorafenib-resistant HCC cells, while HMOX1 overexpression upregulated mRNA expression of ABC transporter expression in HCC cells. Further analysis also revealed that high expression of HMOX1 was associated with shorter OS and DSS in HCC patients. In conclusion, our analysis identified ten hub genes associated with sorafenib resistance in HCC. Further validation studies demonstrated that HMOX1 promoted sorafenib resistance of HCC cells via modulating ABC transporter expression.
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Project description:The MAGE-C1/CT7 encodes a cancer/testis antigen (CTA), is located on the chromosomal region Xq26-27 and is highly polymorphic in humans. MAGE-C1/CT7 is frequently expressed in multiple myeloma (MM) that may be a potential target for immunotherapy in this still incurable disease. MAGEC1/CT7 expression is restricted to malignant plasma cells and it has been suggested that MAGE-C1/CT7 might play a pathogenic role in MM; however, the exact function this protein in the pathophysiology of MM is not yet understood. Our objectives were (1) to clarify the role of MAGE-C1/CT7 in the control of cellular proliferation and cell cycle in myeloma and (2) to evaluate the impact of silencing MAGE-C1/CT7 on myeloma cells treated with bortezomib. Myeloma cell line SKO-007 was transduced for stable expression of shRNA-MAGE-C1/CT7. Downregulation of MAGE-C1/CT7 was confirmed by real time quantitative PCR and western blot. Functional assays included cell proliferation, cell invasion, cell cycle analysis and apoptosis. Western blot showed a 70-80% decrease in MAGE-C1/CT7 protein expression in inhibited cells (shRNA-MAGE-C1/CT7) when compared with controls. Functional assays did not indicate a difference in cell proliferation and DNA synthesis when inhibited cells were compared with controls. However, we found a decreased percentage of cells in the G2/M phase of the cell cycle among inhibited cells, but not in the controls (p<0.05). When myeloma cells were treated with bortezomib, we observed a 48% reduction of cells in the G2/M phase among inhibited cells while controls showed 13% (empty vector) and 9% (ineffective shRNA) reduction, respectively (p<0.01). Furthermore, inhibited cells treated with bortezomib showed an increased percentage of apoptotic cells (Annexin V+/PI-) in comparison with bortezomib-treated controls (p<0.001). We found that MAGE-C1/CT7 protects SKO-007 cells against bortezomib-induced apoptosis. Therefore, we could speculate that MAGE-C1/CT7 gene therapy could be a strategy for future therapies in MM, in particular in combination with proteasome inhibitors.
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Project description:Multiple myeloma (MM) remains an incurable plasma cell cancer characterized by abnormal secretion of monoclonal immunoglobulins. The molecular mechanism that regulates the drug sensitivity of MM cells is being intensively studied. Here, we report an unexpected finding that the protein encoded by neural precursor cell-expressed developmentally downregulated gene 4L (NEDD4L), which is a HECT E3 ligase, binds the 19S proteasome, limiting its proteolytic function and enhancing autophagy. Suppression of NEDD4L expression reduced bortezomib (Bor) sensitivity in vitro and in vivo, mainly through autophagy inhibition mediated by low NEDD4L expression, which was rescued by an autophagy activator. Clinically, elevated expression of NEDD4L is associated with a considerably increased probability of responding to Bor, a prolonged response duration, and improved overall prognosis, supporting both the use of NEDD4L as a biomarker to identify patients most likely to benefit from Bor and the regulation of NEDD4L as a new approach in myeloma therapy.
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Project description:Both transforming growth factor-β (TGF-β) and parathyroid hormone-related protein (PTHrP) regulate important cellular processes, such as apoptosis in the development of hepatocellular carcinoma. However, the mechanisms of regulation of PTHrP by TGF-β are largely unknown. We hypothesized that TGF-β regulates the expression of PTHrP protein through a post-translational mechanism. Using hepatocellular carcinoma cell lines as the in vitro model, we investigated the effects of TGF-β on protein expression and post-translational processing of PTHrP. We found that TGF-β treatment led to protein degradation of PTHrP through the ubiquitin-proteasome-dependent pathway. We also provided evidence to show that Smurf2 was the E3 ligase responsible for the ubiquitination of PTHrP. Furthermore, using immunohistochemistry on human hepatocellular carcinoma specimens and a tissue array, we found that the expression of PTHrP was predominantly in the cancer cells, whereas the expression of TGF-β was present in non-neoplastic liver tissue adjacent to hepatocellular carcinoma. Our findings reveal a novel mechanism whereby TGF-β may regulate PTHrP in hepatocellular carcinogenesis and lack of TGF-β in hepatocellular carcinoma may promote cancer progression. Promotion of PTHrP degradation provides a novel target of therapeutic intervention to sensitize hepatocellular carcinoma cells to cytostatic and/or pro-apoptotic signals.
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Project description:Background:Bortezomib is an approved proteasome inhibitor for the treatment of certain lymphoma subtypes. Two clinical trials investigated bortezomib in patients with malignant pleural mesothelioma (MPM) and failed to improve outcome. We present a potential explanation for this event. Methods:171 patients with MPM were analyzed for their mRNA expression of proteasomal subunits PSMA1, PSMA5, PSMB1, PSMB2, PSMB4 and PSMB5 via qPCR (n=84) or sequencing (n=87 TCGA/cBioPortal data set "Mesothelioma"). Outcome and subunit expression were correlated. Four mesothelial and one fibroblast cell line were treated with bortezomib and cisplatin. Cellular response was measured after 0, 6, 12, 24, 48 and 72 hrs. Enzyme activity of proteasomal subunits was assessed via functional enzyme activity assays. Results:Patients with MPM presented with elevated expression of proteasomal subunits compared to benign controls (p<0.001). PSMB4 correlated with outcome (Cox propotiortional-hazards model (COXPH): p<0.0175, TCGA/cBioPortal data). In cell lines, apoptosis was the main event with a peak after 48 hr incubation for bortezomib or cisplatin. Only two cell lines with comparably low proteasome activity (PSMB2 and PSMB5) responded to 50 nM and 100 nM bortezomib better than to cisplatin (MRC-5, NCI-H2052). MSTO-211H responded to cisplatin only, whereas the other two cell lines were considered therapy resistant (Met-5A, NCI-H2452). Interpretation:Two clinical trials testing bortezomib in MPM failed, although MPM presents with high proteasome expression, which predicts bortezomib sensitivity in several tumors. Bortezomib induced apoptosis in MPM cell lines with low proteasome activity only. Bortezomib is not suitable for the treatment of MPM, and biomarker-based stratification could have improved both clinical trials. Trial registration:NCT00513877 and NCT00458913.
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Project description:Atypical teratoid rhabdoid tumors (ATRTs) are among the most malignant brain tumors in early childhood and remain incurable. Myc-ATRT is driven by the Myc oncogene, which directly controls the intracellular protein synthesis rate. Proteasome inhibitor bortezomib (BTZ) was approved by the Food and Drug Administration as a primary treatment for multiple myeloma. This study aimed to determine whether the upregulation of protein synthesis and proteasome degradation in Myc-ATRTs increases tumor cell sensitivity to BTZ. We performed differential gene expression and gene set enrichment analysis on matched primary and recurrent patient-derived xenograft (PDX) samples from an infant with ATRT. Concomitant upregulation of the Myc pathway, protein synthesis and proteasome degradation were identified in recurrent ATRTs. Additionally, we found the proteasome-encoding genes were highly expressed in ATRTs compared with in normal brain tissues, correlated with the malignancy of tumor cells and were essential for tumor cell survival. BTZ inhibited proliferation and induced apoptosis through the accumulation of p53 in three human Myc-ATRT cell lines (PDX-derived tumor cell line Re1-P6, BT-12 and CHLA-266). Furthermore, BTZ inhibited tumor growth and prolonged survival in Myc-ATRT orthotopic xenograft mice. Our findings suggest that BTZ may be a promising targeted therapy for Myc-ATRTs.
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Project description:Kidney fibrosis and fibrogenesis significantly exacerbate chronic kidney disease (CKD) progression and are essential therapeutic targets. Bortezomib (BZM) is a proteasome inhibitor used for the treatment of multiple myeloma (MM). Several studies have demonstrated that BZM attenuates renal impairment in patients with MM, although this effect is generally considered to be the result of MM remission. Recently, several studies on BZM reported anti-fibrotic effects on liver and skin in experimental animal models. However, its effect on renal fibrosis has yet to be examined. Here, we investigated the anti-fibrotic effects of BZM in an experimental mouse model of fibrosis that uses aristolochic acid I (AA). Ten weeks of AA administration with BZM treatment twice a week significantly attenuated AA-induced renal dysfunction and albuminuria, reduced the expression of renal fibrosis-related proteins and kidney injury markers, such as αSMA, Kim1, and Ngal, and prevented renal fibrosis at the level of histopathology. Furthermore, pathological activation of TGFβ1-Smad3 signaling and apoptosis, essential pathophysiological causes of AA-induced nephropathy (AAN), were ameliorated by BZM, suggesting this mechanism may be involved in improving fibrosis in AAN. In conclusion, BZM directly inhibits renal fibrosis in CKD via suppression of TGFβ1-Smad3 signaling and is promising in terms of drug repositioning.
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Project description:Researches have pointed that piplartine inhibits the proliferation of hepatocellular carcinoma (HCC) cells, however, the underlying mechanisms has not been well defined. Currently, more and more studies have pointed out that circRNAs can regulate tumor cell proliferation, involve in the tumorigenesis mechanism of various tumors. In this study, we explored whether piplartine may participate in the development of HCC through the regulation of ability of HCC cell proliferation by circRNA. Based on the chip analysis, we selected candidate circRNAs that are highly correlated with HCC. CircRNA expression in OSCC cells treated with piplartine was detected by qRT-PCR. We found that only the expression of hsa_circ_100338 (circ-100338) was observably reduced. The expression characteristics of circ-100338 in HCC cell lines were also verified by qRT-PCR. Subsequently, whether or notcirc-100338 can regulate ZEB1 via competitively binding to miR-141-3p was determined by the RIP assay and dual luciferase reporter gene assay. The effect of the circ-100338/miR-141-3p/ZEB1 axis on the proliferation of HCC cell was tested by EdU and CCK-8 assay. Results showed that circ-100338 expression was observably increased in HCC cell lines. Simultaneously, circ-100338 can regulate the expression of ZEB1by competitively binding to miR-141-3p. Moreover high expression of circ-100338 can stimulate the proliferation of HCC cells. Our current study revealed that circ-100338 played as a ceRNA in promoting the progression of HCC by sponging miR-141-3p, while piplartine can participate in the development of HCC by inhibiting the expression of circ-100338.
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Project description:CIP2A is an oncoprotein that upregulates p-Akt and promotes cancer cell proliferation and survival. The proteasome inhibitor bortezomib has been shown to reduce CIP2A and lead to cell apoptosis. Here; we modified the functional group of bortezomib to generate a series of novel compounds and conducted a structure-activity relationship (SAR) study. The results showed that compound 1 was able to repress CIP2A expression and cell apoptosis in the same manner as bortezomib, but with less potency in inhibition of proteasome activity. This finding provides a new direction for the design of CIP2A inhibitors.
| S-EPMC6269665 | biostudies-literature
Project description:BACKGROUND:The high incidence and mortality of lung tumours is a major health problem. Therefore, the identification both of biomarkers predicting efficacy for therapies in use and of novel efficacious therapeutic agents is crucial to increase patient survival. MAP17 (PDZK1IP1) is a small membrane-bound protein whose upregulation is reported as a common feature in tumours from diverse histological origins. Furthermore, MAP17 is correlated with tumour progression. METHODS:We assessed the expression of MAP17 in preclinical models, including cell lines and patient-derived xenografts (PDXs), assessing its correlation with sensitivity to different standard-of-care drugs in lung adenocarcinoma, as well as novel drugs. At the clinical level, we subsequently correlated MAP17 expression in human tumours with patient response to these therapies. RESULTS:We show that MAP17 expression is induced during lung tumourigenesis, particularly in lung adenocarcinomas, and provide in vitro and in vivo evidence that MAP17 levels predict sensitivity to therapies currently under clinical use in adenocarcinoma tumours, including cisplatin, carboplatin and EGFR inhibitors. In addition, we show that MAP17 expression predicts proteasome inhibitor efficacy in this context and that bortezomib, an FDA-approved drug, may be a novel therapeutic approach for MAP17-overexpressing lung adenocarcinomas. CONCLUSIONS:Our results indicate a potential prognostic role for MAP17 in lung tumours, with particular relevance in lung adenocarcinomas, and highlight the predictive pot0065ntial of this membrane-associated protein for platinum-based therapy and EGFR inhibitor efficacy. Furthermore, we propose bortezomib treatment as a novel and efficacious therapy for lung adenocarcinomas exhibiting high MAP17 expression.
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