Glutathione <i>S</i>‐transferase omega 1 inhibition activates <scp>JNK</scp>‐mediated apoptotic response in breast cancer stem cells

Marumudi, Kanakaraju; Debnath, Sudhan; Goswami, Kalyan; Bhoj, Priyanka; Chandak, Hemant S.; Bahekar, Sandeep P.; Das, Amitava

doi:10.1111/febs.14813

Cited by 39 publications

(34 citation statements)

References 59 publications

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“…Consistent with that, pathways essential for tumor microenvironment, such as angiogenesis and ECM-receptor interactions, were also dysregulated in response to GSTO1 KO. A recent study also showed that GSTO1 inhibition resulted in decreased migration and invasion in sorted breast cancer stem cells (47). In conclusion, our results demonstrate that GSTO1 inhibit 3D cell growth, influence gene sets involved in angiogenesis, cell adhesion, and interaction with the surrounding ECM, and play an important role in modifying tumor microenvironment.…”

Section: Discussionsupporting

confidence: 75%

Deletion of Glutathione S-Transferase Omega 1 Activates Type I Interferon Genes and Downregulates Tissue Factor

Bankhead

Tian

et al. 2020

Cancer Research

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◥ GST omega 1 (GSTO1) is an atypical GST isoform that is overexpressed in several cancers and has been implicated in drug resistance. Currently, no small-molecule drug targeting GSTO1 is under clinical development. Here we have validated GSTO1 as an impactful target in oncology. Transcriptional profiling coupled with proteomics uncovered novel pharmacodynamic markers and cellular pathways regulated by GSTO1. CRISPR/Cas9 GSTO1 knockout (KO) cell lines failed to form tumors or displayed growth delay in vivo; they also formed smaller 3D spheroids in vitro. Multiomics analysis in GSTO1 KO cells found a strong positive correlation with cell adhesion molecules and IFN response pathways and a strong negative correlation with Myc transcriptional signature. In addition, several clinically used drugs showed significant synthetic lethality with loss or inhibition of GSTO1. Transcription and protein expression of tissue factor (gene name, F3) were downregulated in response to GSTO1 KO. F3 is associated with poor patient survival and promotion of tumor progression in multiple cancers and is a known risk factor for metastasis. Transcription of F3 was regulated by IL1b, whose secretion decreased upon inhibition of GSTO1, suggesting that IL1b links GSTO1 expression and F3 transcription. In summary, our results implicate GSTO1 as a potential therapeutic target in cancer and offer new mechanistic insights into its significant role in cancer progression. Significance: These findings validate GSTO1 as a therapeutic target in cancer and implicate GSTO1 in the modulation of tumor growth, immune responses, and expression of F3.

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Section: Discussionsupporting

confidence: 75%

Deletion of Glutathione S-Transferase Omega 1 Activates Type I Interferon Genes and Downregulates Tissue Factor

Bankhead

Tian

et al. 2020

Cancer Research

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“…Therefore, further investigations into the mechanism underlying NSCLC development and progression are essential for improving the treatment of NSCLC. The expression levels of GSTO1 were previously discovered to be upregulated in various types of cancer, including lymphoma, melanoma and colorectal cancer (7,16,21). However, to the best of our knowledge, the role of GSTO1 in NSCLC has not been investigated.…”

Section: Discussionmentioning

confidence: 97%

“…Glutathione S-transferases (GSTs) are enzymes that can combine with glutathione and various endogenous and exogenous metabolites during biotransformation (7). In humans, seven cytoplasmic GST classes have been identified, including α, μ, σ, π, τ, ζ and ω (8).…”

Section: Introductionmentioning

confidence: 99%

“…Chuang et al (14) illustrated that the expression levels of GSTO1 were upregulated in human bladder cancer cells. Moreover, GSTO1 has been revealed to contribute to cell growth, death, migration and invasion in several types of cancer cell (7,(15)(16)(17). For example, Wang et al (15) reported that GSTO1 was upregulated in cutaneous malignant melanoma (CMM) tissues and cells, where it contributed to CMM cell growth, migration and invasion.…”

Section: Introductionmentioning

confidence: 99%

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Glutathione S‑transferase ω 1 promotes the proliferation, migration and invasion, and inhibits the apoptosis of non‑small cell lung cancer cells, via the JAK/STAT3 signaling pathway

2020

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Glutathione S-transferase ω 1 (GSTO1) expression levels have been discovered to be upregulated in various types of cancer. However, to the best of our knowledge, the role of GSTO1 in non-small cell lung cancer (NSCLC) has not been investigated. The present study aimed to investigate the role of GSTO1 in NSCLC and to determine the potential molecular mechanism. GSTO1 expression levels in A549 cells were knocked down using short hairpin RNA and GSTO1 overexpression in H2122 cells was achieved using cDNA constructs. Reverse transcription-quantitative PCR was used to analyze the mRNA expression levels of GSTO1. Cell proliferation was determined using a Cell Counting Kit-8 assay, whereas cell migration and invasion were analyzed using Transwell assays. Flow cytometric analysis was performed to determine the levels of cell apoptosis. The expression levels of GSTO1, Bax, caspase 3, JAK and STAT3 were analyzed using western blotting. The results revealed that GSTO1 overexpression significantly promoted the proliferation, migration and invasion, and inhibited the apoptosis of H2122 cells, whereas the opposite trend was achieved in A549 cells with GSTO1 knockdown. GSTO1 overexpression also significantly increased the phosphorylation levels of JAK and STAT3, whereas the knockdown of GSTO1 promoted the opposite effects. In conclusion, the findings of the present study indicated that GSTO1 may serve as an oncogene in NSCLC. The results suggested that GSTO1 may have an important role in NSCLC by regulating the JAK/STAT3 signaling pathway. Therefore, inhibiting the expression levels of GSTO1 may represent a potential novel therapeutic strategy for NSCLC.

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“…Doxorubicin was used as a positive control. The optical density at 510 nm was measured using a multimode reader (Perkin Elmer, Germany) and percent inhibition with IC-50 was calculated using GraphPad prism 6.0 as described previously (Manupati et al 2019).…”

Section: Antiproliferative Activitymentioning

confidence: 99%

In vitro and in silico antioxidant and antiproliferative activity of rhizospheric fungus Talaromyces purpureogenus isolate-ABRF2

Sahu

Kaushik

Das

et al. 2020

Bioresour. Bioprocess.

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The present study evaluated the potential biological activities of rhizospheric fungi isolated from the Achanakmar Biosphere Reserve, India. Fungus, Talaromyces purpureogenus isolate-ABRF2 from the soil of the Achanakmar biosphere was characterized by using morphological, biochemical and molecular techniques. Fungus was screened for the production of secondary metabolites using a specific medium. The metabolites were extracted using a suitable solvent and each fraction was subsequently evaluated for their antioxidant, antimicrobial, antiproliferative and anti-aging properties. The ethanolic extract depicted the highest antioxidant activity with 83%, 79%, 80% and 74% as assessed by ferric reducing power, 2,2-diphenyl 1-picrylhydrazyl, 2,2′-azino-bis3-ethylbenzthiazoline-6-sulfonic and phosphomolybdenum assays, respectively. Similarly, ethanolic extracts depicted marked antimicrobial activity as compared with standard antibiotics and antifungal agents as well as demonstrated significant antiproliferative property against a panel of mammalian cancer cell lines. Furthermore, different fractions of the purified ethanolic extract obtained using adsorption column chromatography were evaluated for antiproliferative property and identification of an active metabolite in the purified fraction using gas chromatography-mass spectroscopy and nuclear magnetic resonance techniques yielded 3-methyl-4-oxo-pentanoic acid. Thus, the present study suggests that the active metabolite 3-methyl-4-oxo-pentanoic acid extracted from Talaromyces purpureogenus isolate-ABRF2 has a potential antiproliferative, anti-aging, and antimicrobial therapeutic properties that will be further evaluated using in vivo studies in future.

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Glutathione S‐transferase omega 1 inhibition activates JNK‐mediated apoptotic response in breast cancer stem cells

Cited by 39 publications

References 59 publications

Deletion of Glutathione S-Transferase Omega 1 Activates Type I Interferon Genes and Downregulates Tissue Factor

Deletion of Glutathione S-Transferase Omega 1 Activates Type I Interferon Genes and Downregulates Tissue Factor

Glutathione S‑transferase ω 1 promotes the proliferation, migration and invasion, and inhibits the apoptosis of non‑small cell lung cancer cells, via the JAK/STAT3 signaling pathway

In vitro and in silico antioxidant and antiproliferative activity of rhizospheric fungus Talaromyces purpureogenus isolate-ABRF2

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