The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA809423 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18105718_1.fastq.gz | Fastqsanger.gz | |||
| SRR18105718_2.fastq.gz | Fastqsanger.gz | |||
| SRR18105719_1.fastq.gz | Fastqsanger.gz | |||
| SRR18105719_2.fastq.gz | Fastqsanger.gz | |||
| SRR18105720_1.fastq.gz | Fastqsanger.gz |
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Project description:Transient receptor potential channel melastatin 2 (TRPM2) is highly expressed in cancer and has an essential function in preserving viability through maintenance of mitochondrial function and antioxidant response. Here, the role of TRPM2 in cell survival was examined in neuroblastoma cells deleted of TRPM2 with CRISPR technology. Viability was significantly decreased in TRPM2 knockout after doxorubicin treatment. RNA sequence analysis and RT-qPCR revealed reduced RNAs encoding master transcription regulators FOXM1 and E2F1/2 and downstream cell cycle targets including Cyclin B1, CDK1, PLK1, and CKS1. CHIP analysis demonstrated decreased FOXM1 binding to their promoters. Western blotting confirmed decreased expression, and increased expression of CDK inhibitor p21, a CKS1 target. In cells with TRPM2 deletion, cell cycle progression to S and G2/M phases was reduced after treatment with doxorubicin. RNA sequencing also identified decreased DNA repair proteins in cells with TRPM2 deletion after doxorubicin treatment, and DNA damage was increased. Wild type TRPM2 but not Ca2+-impermeable mutant E960D, restored live cell number and reconstituted expression of E2F1, FOXM1, and cell cycle/DNA repair proteins. FOXM1 expression alone restored viability. TRPM2 is a potential therapeutic target to reduce tumor proliferation and increase doxorubicin sensitivity through modulation of FOXM1, E2F1, and cell cycle/DNA repair proteins.
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Project description:Transient receptor potential channel TRPM2 is highly expressed in many cancers and involved in regulation of key physiological processes including mitochondrial function, bioenergetics, and oxidative stress. In Stage 4 non-MYCN amplified neuroblastoma patients, high TRPM2 expression is associated with worse outcome. Here, neuroblastoma cells with high TRPM2 expression demonstrated increased migration and invasion capability. RNA sequencing, RT-qPCR, and Western blotting demonstrated that the mechanism involved significantly greater expression of integrins α1, αv, β1, and β5 in cells with high TRPM2 expression. Transcription factors HIF-1α, E2F1, and FOXM1, which bind promoter/enhancer regions of these integrins, were increased in cells with high TRPM2 expression. Subcellular fractionation confirmed high levels of α1, αv, and β1 membrane localization and co-immunoprecipitation confirmed the presence of α1β1, αvβ1, and αvβ5 complexes. Inhibitors of α1β1, αvβ1, and αvβ5 complexes significantly reduced migration and invasion in cells highly expressing TRPM2, confirming their functional role. Increased pAktSer473 and pERKThr202/Tyr204, which promote migration through mechanisms including integrin activation, were found in cells highly expressing TRPM2. TRPM2 promotes migration and invasion in neuroblastoma cells highly expressing TRPM2 through modulation of integrins together with enhancing cell survival, negatively affecting patient outcome and providing the rationale for TRPM2 inhibition in anti-neoplastic therapy.
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Project description:Transient receptor potential channel melastatin 2 (TRPM2) is highly expressed in cancer and has an essential function in preserving viability through maintenance of mitochondrial function and antioxidant response. Here, the role of TRPM2 in cell survival was examined in neuroblastoma cells with TRPM2 deletion with CRISPR technology. Viability was significantly decreased in TRPM2 knockout after doxorubicin treatment. RNA sequence analysis and RT-qPCR revealed reduced RNAs encoding master transcription regulators FOXM1 and E2F1/2 and downstream cell cycle targets including Cyclin B1, CDK1, PLK1, and CKS1. CHIP analysis demonstrated decreased FOXM1 binding to their promoters. Western blotting confirmed decreased expression, and increased expression of CDK inhibitor p21, a CKS1 target. In cells with TRPM2 deletion, cell cycle progression to S and G2/M phases was reduced after treatment with doxorubicin. RNA sequencing also identified decreased DNA repair proteins in cells with TRPM2 deletion after doxorubicin treatment, and DNA damage was increased. Wild type TRPM2, but not Ca2+-impermeable mutant E960D, restored live cell number and reconstituted expression of E2F1, FOXM1, and cell cycle/DNA repair proteins. FOXM1 expression alone restored viability. TRPM2 is a potential therapeutic target to reduce tumor proliferation and increase doxorubicin sensitivity through modulation of FOXM1, E2F1, and cell cycle/DNA repair proteins.
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Project description:The human ion channel TRPM2 modulates migration and invasion in neuroblastoma through regulation of integrin expression
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Project description:Cellular senescence wreaks defects in the aging organism. In this study, we co-treated two chemicals: rho-associated protein kinase (ROCK) inhibitor (Y-27632) and ataxia telangiectasia mutated (ATM) inhibitor (KU-60019) to overcome senescence more efficaciously, these two chemicals are already revealed to have senomorphic effects, suppressing senescent phenotypes. We find out that cocktail treatment synergistically alleviates diverse senescent phenotypes in senescent human dermal fibroblast cells. Through transcriptomic approach, FOXM1 and E2F1 are identified as key transcription factor of synergism to normalize senescent cells, of which activities are attenuated by senescence both in vitro and in vivo, but revitalized by co-treatment. Activation of FOXM1 precedes activation of E2F1 and mediates transcription of numerous genes totally shut off by cellular senescence, including E2F1. After that, E2F1 participates in transcriptomic change. For that, Cyclin-dependent kinase (CDKs), where are the confluences of both ATM-Chk2-CDKs and ROCK-Akt-CDKs signaling axes, are direct regulators of these transcription factors. Surprisingly, canonical aging-related CDK inhibitors have nothing to do with the onset of senomorphism. As the order of activations of FOXM1 and E2F1 that are in charge of G2 and G1 phase transition respectively, chemical combination releases senescent cell arrest in order of G2 then G1. Altogether, our data provide new insight into the way of amelioration of aging via pivotal cell cycle transcription factors, FOXM1 and E2F1, which are synergistically stimulated by inhibiting senescence-associated kinases, ATM and ROCK.
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