Ambroxol Induced Myeloma Cell Death by Inhibiting Autophagy
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ABSTRACT:
PROVIDER: PRJNA1075452 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27941509_1.fastq.gz | Fastqsanger.gz | |||
| SRR27941509_2.fastq.gz | Fastqsanger.gz | |||
| SRR27941510_1.fastq.gz | Fastqsanger.gz | |||
| SRR27941510_2.fastq.gz | Fastqsanger.gz | |||
| SRR27941511_1.fastq.gz | Fastqsanger.gz |
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Project description:Recently, newly developed drugs have significantly improved prognosis of patients with multiple myeloma (MM). However, most patients relapsed sooner or later, and thus, MM is still an incurable hematological malignancy. In addition, serious adverse events occasionally hamper to continue treatment. Exploitation of the new drugs that potentiate the anti-tumor activities and alleviate the adverse effects of the existing drugs is needed. Here, we found by drug repositioning that ambroxol hydrochloride (ambroxol) induces apoptosis of MM cells. Interestingly, turnover assay and reporter assay showed that ambroxol inhibits late stage of autophagy. Transmission Electron Microscope (TEM) observation also showed that MM cells treated with ambroxol revealed accumulation of autophagy vesicles in cytoplasm, supporting the result of inhibition of late stage autophagy. Existing anti-MM drugs demonstrate various effects on autophagy; panobinostat, a histone deacetylase inhibitor, induced autophagy while bortezomib and lenalidomide did not. Ambroxol revealed synergistic anti-myeloma effect with panobinostat because ambroxol was considered to inhibit activation of panobinostat-induced autophagy and also downregulated MCL1 expression. In KMS 11-xenograft model, ambroxol alone significantly delayed tumor growth, and synergistically enhanced panobinostat-induced inhibition of tumor growth. Interestingly, concomitant use of ambroxol with panobinostat alleviated panobinostat-induced diarrhea. Gene set enrichment analyses (GSEAs) and pathway analysis also showed that ambroxol increased expression of the genes related to autophagy inhibition and unfolded protein response. These results suggested that autophagy is a promising therapeutic target for multiple myeloma.
2025-02-16 | GSE255564 | GEO
Project description:We performed a loss-of-function, RNA interference screen to define new therapeutic targets in multiple myeloma, a genetically diverse plasma cell malignancy. Unexpectedly, we discovered that all myeloma lines require caspase-10 for survival, irrespective of their genetic abnormalities. The transcription factor IRF4 induces both caspase-10 and its associated protein cFLIPL in myeloma, generating a protease that does not induce apoptosis but rather blocks an autophagy-dependent cell death pathway. Caspase-10 inhibits autophagy by cleaving the BCL2-interacting protein BCLAF1, itself a strong inducer of autophagy that acts by displacing beclin-1 from BCL2. While myeloma cells require a basal level of autophagy for survival, caspase-10 tempers this response to avoid cell death. Drugs that disrupt this vital balance may have therapeutic potential in myeloma. To generate a gene expression signature of caspase 10 signaling in multiple myeloma, cell lines (SKMM1 n=16, KMS12 n=8 and H929 n=12) were transduced with retroviral vectors expressing either shCasp10-2 or shCasp10-3. Similarly, lymphoma cell lines (OCI-Ly7 n=2 and OCI-Ly19 n=2) were transduced and used as a control. Following puromycin selection, shRNA expression was induced for 24 to 120 hours and gene expression was measured, comparing uninduced (Cy3) to induced (Cy5) cells, using lymphochip microarrays. Biological repeats were performed of H929 and SKMM1 samples.
2013-03-13 | E-GEOD-43878 | biostudies-arrayexpress
Project description:We performed a loss-of-function, RNA interference screen to define new therapeutic targets in multiple myeloma, a genetically diverse plasma cell malignancy. Unexpectedly, we discovered that all myeloma lines require caspase-10 for survival, irrespective of their genetic abnormalities. The transcription factor IRF4 induces both caspase-10 and its associated protein cFLIPL in myeloma, generating a protease that does not induce apoptosis but rather blocks an autophagy-dependent cell death pathway. Caspase-10 inhibits autophagy by cleaving the BCL2-interacting protein BCLAF1, itself a strong inducer of autophagy that acts by displacing beclin-1 from BCL2. While myeloma cells require a basal level of autophagy for survival, caspase-10 tempers this response to avoid cell death. Drugs that disrupt this vital balance may have therapeutic potential in myeloma.
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Project description:Transcriptomes analysis for the regulation of Z36 induced autophagy in HeLa cell death
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Project description:Z36 is a small molecule that induces Beclin1-dependent autophagy and autophagic cell death in HeLa cells. This is different from the typical autophagy induced by Rapamycin, which plays a protective role for cells. To gain insights into the regulation of autophagy in cell death by Z36, high-throughput RNA-sequencing were performed on HeLa cells treated with DMSO (as control), Z36 and Rapamycin. Two biological replaces were collected for each of the three conditions. The sequencing generated more than 30 million reads for each sample. RNA-seq data showed that there were about 3000 DEGs with over 2 folds changes (|log2 (fold change)| > 1 & P value < 0.05) in Z36 treated cells versus those of DMSO. On the contrary, there were only 200 DEGs for cells treated with Rapamycin. Noteworthily, expression levels of autophagic genes were significantly changed in Z36 treated cells, and the change pattern was different from Rapamycin treated ones. 8 of the ATG genes were up-regulated for more than 2 folds (log2 > 1) after Z36 treatment, while Rapa only caused small changes for the ATG genes, with the highest log2 change of 0.7. These study indicate that Z36 leads to significant modulation of a large number of genes at transcriptional level.
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Project description:Steroid 5α-reductase type I (SRD5A1) is a validated oncogene in many sex hormone-related cancers, but its role in multiple myeloma (MM) remains unknown. Based on gene expression profiling of sequential MM samples during disease course, we found that high SRD5A1 expression was correlated with progression and poor prognosis in MM patients. In this study, we assessed the SRD5A1 function in promoting MM cell growth, cell cycle and tumorigenesis by using different human MM cell lines, the xenograft mouse and 5TMM mouse models. Applying lentivirus-mediated short-hairpin RNA (shRNA) method, inducible knockdown of SRD5A1 inhibited myeloma cell growth and induced cell apoptosis as well as autophagy. Meanwhile, the SRD5A1 knockdown-induced apoptosis was aggravated by the autophagy inhibitor 3-methyladenine. Mechanistically, SRD5A1 downregulation simultaneously regulated both the Bcl-2 family proteins mediated apoptosis and the autophagic process via PI3K/Akt/mTOR signaling pathway in MM cells. We also evaluated the therapeutic effect of SRD5A1 inhibitor, Dutasteride, on improving the survival rate of MM mouse model. To summarize, our findings demonstrate that SRD5A1 may serve as a biomarker for MM progression and prognosis, indicating that the dual autophagy-apoptosis regulatory SRD5A1 is a potential target for future therapies in MM patients.
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