Targeting ITGB4/SOX2-driven cancer stem cells using proteasome inhibitors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA947250 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The transcription factor SOX2 required for pluripotency, is amplified in 40% of the lung squamous cell carcinoma (LUSC) cases. However, a long-term survival analysis using TCGA cohorts of LUSC patients revealed no significant differences between high versus low SOX2 expressing cases. The treatment options for irresectable LUSC are limited to chemotherapy where carboplatin or cisplatin is given in combination with gemcitabine. However, drug resistance remains a serious concern. We previously showed integrin β4 (ITGB4) and paxillin (PXN) play a critical role in platinum resistance in LUAD. Heterogenous NSCLC cells that up-regulate ITGB4 and PXN epigenetically, can switch phenotypes from cisplatin sensitive to tolerant. However, the significance of ITGB4 expression in SOX2 driven cancer stem cells (CSCs) in NSCLC remains unappreciated. In this study, we isolated CSCs from LUSC patients and characterized them. We elucidated the significance of ITGB4 and SOX2 expression in maintaining the stemness of CSCs and their response to cisplatin treatment. Finally, we showed that the proteasome inhibitor carfilzomib (CFZ) targets SOX2 dependent CSCs and this function of CFZ is independent of its proteasome inhibitory function.
2023-08-21 | GSE227899 | GEO
Project description:This study investigates the role of integrin β4 (ITGB4) and stemness-associated factor SOX2 in platinum resistance in lung squamous cell carcinoma (LUSC). The expression of SOX2 and ITGB4 is found to be high in all LUSC subtypes, but the impact of ITGB4 expression on overall patient survival varies by subtype. Cancer stem cells (CSCs) isolated from LUSC patients were found to be resistant to cisplatin, but knocking down ITGB4 or SOX2 sensitized them to cisplatin. Carfilzomib (CFZ) synergized with cisplatin and suppressed CSC growth by inhibiting ITGB4 and SOX2 expression. Additionally, CFZ was found to inhibit SOX2 expression epigenetically by inhibiting histone acetylation at the SOX2 promoter site. CFZ also suppressed the growth of SOX2-dependent small cell lung cancer cells in vitro and in vivo. The study highlights the unique function of CFZ as a transcriptional suppressor of SOX2, independent of its proteasome inhibitory function.
| S-EPMC10405066 | biostudies-literature
Project description:Epigenetic modifying enzymes are commonly mutated in diffuse large B cell lymphoma (DLBCL), suggesting that epigenetic regulation is an important factor in DLBCL pathogenesis and a potential target for therapy. We developed resistant cell lines to histone deacetylase inhibitors (HDACi), one such epigenetic therapy, in order to define mechanisms of response and resistance. Strikingly, using gene expression and metabolic profiling, we found that development of HDACi resistance was associated with differentiation toward a plasmablast-like phenotype. Differentiation correlated with decreased B cell receptor signaling, increased ER stress and activation of the unfolded protein response, and increased sensitivity to proteasome inhibitors. Importantly, we found evidence of differentiation in lymphoma biopsies from patients treated with HDACi. Together, these data show, for the first time, that HDACi are differentiating agents in lymphoma and may be used to prime DLBCL for targeted therapy including proteasome inhibitors. Gene expression in DLBCL cells from tumor biopsies after 15 days panobinostat therapy
2016-08-01 | E-GEOD-59308 | biostudies-arrayexpress
Project description:Synthetic IDE inhibitors sensitize and reverse acquired resistance of multiple myeloma cells to proteasome inhibitors
| PRJNA763933 | ENA
Project description:Epigenetic modifying enzymes are commonly mutated in diffuse large B cell lymphoma (DLBCL). Importantly, genetics abnormalities lead to inactivation of HAT, which tilt the balance in favor of decreased protein acetylation in DLBCL cells. This suggests that protein acetylation regulation is an important factor in DLBCL pathogenesis and a potential target for therapy. We developed resistant cell lines to the histone deacetylase inhibitor (HDACi) vorinostat, in order to better define molecular mechanisms of action of HDACi in lymphoma cells. We found that cells resistant to HDACi have increased protein synthesis and proteasomal degradation. Additionally, cells resistant to HDACi have acquired increased susceptibility to proteasome inhibitors and this correlates with activation of the unfolded protein response. Importantly, using transcriptional signatures found in our resistant lymphoma cell line model, we show that tumors from DLBCL patients treated but unresponsive to HDACi therapy undergo similar changes. Together, these data show, for the first time, that HDACi may be used to prime DLBCL for targeted therapy including proteasome inhibitors. Gene expression in U937 cells after 12h exposure to 2µM vorinostat and after development of resistance to 2 µM vorinostat, with and without vorinostat in the media.
2016-06-01 | E-GEOD-58421 | biostudies-arrayexpress
Project description:We compared the expression changes in Ewing sarcoma cell lines following treatment with 2 known 20S proteasome inhibitors versus 2 novel compounds
2017-04-25 | GSE80640 | GEO
Project description:Germline and somatic mutations in BRCA1predispose to breast cancer. We found that proteasome inhibitors can selectively kill BRCA1-depleted cells. The toxic response involves a deregulation of the G1/S cell cycle checkpoint via hyperphosphorylation of RB1, 53BP1-mediated arrest at G2/M checkpoint, and ERN1-mediated unfolded protein response, culminating in a TNF receptor-mediated apoptosis. The study new unexpected molecular functions for BRCA1 protein and opens a novel possibility for the treatment of BRCA1-deficient cancers. We used microarrays to detail the global programme of gene expression underlying the response of BRCA1-deficient cells to proteasome inhibitor bortezomib. We aimed to identify genes that are strongly up- or down-regulated with a combination of BRCA1 knockdown and proteasome inhibition, but none of these treatments alone before the onset of apoptosis. HeLa and U2OS cells were transfected either with a non-targeting or anti-BRCA1 siRNAs (siControl or siBRCA1, respectively), treated with bortezomib for 8 hours, after which RNA was extracted for hybridization on Affymetrix microarray. The following treatments have been performed: (T1) siControl; (T2) siControl + 20 nM bortezomib for 8h; (T3) siBRCA1; (T4) siBRCA1 + 20 nM bortezomib for 8h. All samples were used without replicas. However, all genes showing inconsistent expression pattern between the two cell lines were excluded from further consideration. Selected candidate genes were subject to validation by qRT-PCR.
2015-01-01 | E-GEOD-56280 | biostudies-arrayexpress
Project description:Epigenetic modifying enzymes are commonly mutated in diffuse large B cell lymphoma (DLBCL), suggesting that epigenetic regulation is an important factor in DLBCL pathogenesis and a potential target for therapy. We developed resistant cell lines to histone deacetylase inhibitors (HDACi), one such epigenetic therapy, in order to define mechanisms of response and resistance. Strikingly, using gene expression and metabolic profiling, we found that development of HDACi resistance was associated with differentiation toward a plasmablast-like phenotype. Differentiation correlated with decreased B cell receptor signaling, increased ER stress and activation of the unfolded protein response, and increased sensitivity to proteasome inhibitors. Importantly, we found evidence of differentiation in lymphoma biopsies from patients treated with HDACi. Together, these data show, for the first time, that HDACi are differentiating agents in lymphoma and may be used to prime DLBCL for targeted therapy including proteasome inhibitors.
2016-08-01 | GSE59308 | GEO
Project description:Germline and somatic mutations in BRCA1predispose to breast cancer. We found that proteasome inhibitors can selectively kill BRCA1-depleted cells. The toxic response involves a deregulation of the G1/S cell cycle checkpoint via hyperphosphorylation of RB1, 53BP1-mediated arrest at G2/M checkpoint, and ERN1-mediated unfolded protein response, culminating in a TNF receptor-mediated apoptosis. The study new unexpected molecular functions for BRCA1 protein and opens a novel possibility for the treatment of BRCA1-deficient cancers. We used microarrays to detail the global programme of gene expression underlying the response of BRCA1-deficient cells to proteasome inhibitor bortezomib.
2015-01-01 | GSE56280 | GEO
Project description:Sox2 has been studied in several types of human solid tumors. The investigators found that Sox2 had higher expression level in colorectal cancer and metastatic tissues than normal tissues. So the investigators assumed that whether Sox2 plays an important role in the progression and migration of colon cancer.
| 2124687 | ecrin-mdr-crc