Cucurbitacin I inhibits STAT3, but enhances STAT1 signaling in human cancer cells in vitro through disrupting actin filaments

Guo, Hui; Kuang, Shan; Song, Qiaoling; Liu, Man; Sun, Xiaoxiao; Yu, Qiang

doi:10.1038/aps.2017.99

Cited by 33 publications

(23 citation statements)

References 70 publications

(70 reference statements)

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“…Our results showed that cucurbitacin I had a positive correlation with STAT3 in the central nervous system, meaning that higher expression of STAT3 was correlated with worse response. However, cucurbitacin I had been proved as a potential inhibitor of STAT3 [81,82]. The converse might be explained by the tumor heterogeneity and the drug response was highly cancer-type-dependent.…”

Section: Discussionmentioning

confidence: 99%

Significance of STAT3 in Immune Infiltration and Drug Response in Cancer

et al. 2020

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Signal transducer and activator of transcription 3 (STAT3) is a transcription factor and regulates tumorigenesis. However, the functions of STAT3 in immune and drug response in cancer remain elusive. Hence, we aim to reveal the impact of STAT3 in immune infiltration and drug response comprehensively by bioinformatics analysis. The expression of STAT3 and its relationship with tumor stage were explored by Tumor Immune Estimation Resource (TIMER), Human Protein Altas (HPA), and UALCAN databases. The correlations between STAT3 and immune infiltration, gene markers of immune cells were analyzed by TIMER. Moreover, the association between STAT3 and drug response was evaluated by the Cancer Cell Line Encyclopedia (CCLE) and Cancer Therapeutics Response Portal (CTRP). The results suggested that the mRNA transcriptional level of STAT3 was lower in tumors than normal tissues and mostly unrelated to tumor stage. Besides, the protein expression of STAT3 decreased in colorectal and renal cancer compared with normal tissues. Importantly, STAT3 was correlated with immune infiltration and particularly regulated tumor-associated macrophage (TAM), M2 macrophage, T-helper 1 (Th1), follicular helper T (Treg), and exhausted T-cells. Remarkably, STAT3 was closely correlated with the response to specified inhibitors and natural compounds in cancer. Furthermore, the association between STAT3 and drug response was highly cell line type dependent. Significantly, the study provides thorough insight that STAT3 is associated with immunosuppression, as well as drug response in clinical treatment.

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Section: Discussionmentioning

confidence: 99%

Significance of STAT3 in Immune Infiltration and Drug Response in Cancer

et al. 2020

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“…Aberrantly active STAT3 promotes tumorigenesis, drug resistance, and metastasis in NSCLC . Downstream signaling effects of the STAT3 pathway can contribute to lung cancer and currently several STAT3 inhibitors show substantial anticancer and antiangiogenic effects . Finding novel agents with STAT3 suppressive activity is vitally important to improve NSCLC treatment.…”

Section: Introductionmentioning

confidence: 99%

Scutellarin suppresses proliferation and promotes apoptosis in A549 lung adenocarcinoma cells via AKT/mTOR/4EBP1 and STAT3 pathways

Cao

Liu

et al. 2019

Thoracic Cancer

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Background Scutellarin (SCU), a flavonoid isolated from Erigeron breviscapus (Vant.) Hand.‐Mazz., increases autophagy and apoptosis in the adenocarcinoma A549 cell line, which is resistant to cisplatin. However, whether SCU alone has antitumor activity against non‐small cell lung cancer (NSCLC) is unknown. Methods Cell Counting Kit‐8, flow cytometry, colony formation, Hoechst 33258 staining, and Western blot analyses were used to examine the proliferation and apoptosis of A549 cells treated with SCU and the possible molecular mechanisms. Results The cell viability assay indicated that SCU markedly suppressed the proliferation of A549 cells in concentration and time‐dependent manners. SCU caused significant G0/G1 phase arrest and apoptosis, as evidenced by flow cytometric analyses, Hoechst 33258 staining, and Western blot analyses of cyclin D1, cyclin E, BCL‐2, cleaved‐caspase‐3, and BAX. Furthermore, SCU treatment reduced the level of pan‐AKT, phosphorylated (p)‐mTOR, mTOR, BCL‐XL, STAT3, and p‐STAT3, and increased the level of 4EBP1. Conclusions SCU can suppress proliferation and promote apoptosis in A549 cells through AKT/mTOR/4EBP1 and STAT3 pathways. This suggests that SCU may be developed into a promising antitumor agent for treating NSCLC.

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“…Samples were treated with B6, AZD1480, or DMSO for 30 min at 37 °C before incubation with biotinylated FLT3 (Cell Signaling Technology, Danvers, MA, USA) for 1 h at 37 °C. Samples were then processed following the protocol for the HTScan JAK2 Kinase Assay Kit [ 24 ].…”

Section: Methodsmentioning

confidence: 99%

3-Deoxy-2β,16-dihydroxynagilactone E, a natural compound from Podocarpus nagi, preferentially inhibits JAK2/STAT3 signaling by allosterically interacting with the regulatory domain of JAK2 and induces apoptosis of cancer cells

Yao

Yang

2019

Acta Pharmacol Sin

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The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, especially the JAK2/STAT3 pathway, play vital roles in the development of many malignancies. Overactivation of STAT3 promotes cancer cell survival and proliferation. Therefore, the JAK2/STAT3-signaling pathway has been considered a promising target for cancer therapy. In this study, we identified a natural compound 3-deoxy-2β,16-dihydroxynagilactone E (B6) from the traditional Chinese medicinal plant Podocarpus nagi as a potent inhibitor of STAT3 signaling. B6 preferentially inhibited the phosphorylation of STAT3 by interacting with and inactivating JAK2, the main upstream kinase of STAT3. B6 dose-dependently inhibited IL-6-induced STAT3 signaling with an IC 50 of 0.2 μM. In contrast to other JAK2 inhibitors, B6 did not interact with the catalytic domain but instead with the FERM-SH2 domain of JAK2. This interaction was JAK-specific since B6 had little effect on other tyrosine kinases. Furthermore, B6 potently inhibited the growth and induced apoptosis of MDA-MB-231 and MDA-MB-468 breast cancer cells with overactivated STAT3. Taken together, our study uncovers a novel compound and a novel mechanism for the regulation of JAK2 and offers a new therapeutic approach for the treatment of cancers with overactivated JAK2/STAT3.

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Cucurbitacin I inhibits STAT3, but enhances STAT1 signaling in human cancer cells in vitro through disrupting actin filaments

Cited by 33 publications

References 70 publications

Significance of STAT3 in Immune Infiltration and Drug Response in Cancer

Significance of STAT3 in Immune Infiltration and Drug Response in Cancer

Scutellarin suppresses proliferation and promotes apoptosis in A549 lung adenocarcinoma cells via AKT/mTOR/4EBP1 and STAT3 pathways

3-Deoxy-2β,16-dihydroxynagilactone E, a natural compound from Podocarpus nagi, preferentially inhibits JAK2/STAT3 signaling by allosterically interacting with the regulatory domain of JAK2 and induces apoptosis of cancer cells

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