Dataset Information

Direct Targeting of CREB1 with Imperatorin Inhibits TGF?2-ERK Signaling to Suppress Esophageal Cancer Metastasis.

ABSTRACT: Metastasis accounts for 90% of cancer death worldwide, and effective therapeutic strategies are lacking. The aim of this work is to identify the key drivers in tumor metastasis and screen therapeutics for treatment of esophageal squamous cell carcinoma (ESCC). Gene Ontology analysis of The Cancer Genome Atlas (TCGA) gene expression datasets of ESCC patients with or without lympy metastasis identifies that TGF?2 is highly enriched in the pathways essential for tumor metastasis and upregulates in the metastatic ESCC tumors. High TGF?2 expression in ESCC correlates with metastasis and patient survival, and functionally contributes to tumor metastasis via activating extracellular signal-regulated kinases (ERK) signaling. By screening of a library consisting of 429 bioactive compounds, imperatorin is verified as a novel TGF?2 inhibitor, with robustly suppressive effect on tumor metastasis in multiple mice models. Mechanistically, direct binding of imperatorin and CREB1 inhibits phosphorylation, nuclear translocation of CREB1, and its interaction with TGF?2 promoter, represses TGF?2 expression and fibroblasts-secreted CCL2, and then inactivates ERK signaling to block cancer invasion and abrogates the paracrine effects of fibroblasts on tumor angiogenesis and metastasis. Overall, the findings suggest the use of TGF?2 as a diagnostic and prognostic biomarker and therapeutic target in ESCC, and supports the potential of imperatorin as a novel therapeutic strategy for cancer metastasis.

SUBMITTER: Xu WW

PROVIDER: S-EPMC7435243 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Direct Targeting of CREB1 with Imperatorin Inhibits TGF<i>β</i>2-ERK Signaling to Suppress Esophageal Cancer Metastasis.

Xu Wen Wen WW Huang Zhi-Hao ZH Liao Long L Zhang Qi-Hua QH Li Jun-Qi JQ Zheng Can-Can CC He Yan Y Luo Ting-Ting TT Wang Yang Y Hu Hui-Fang HF Zuo Qian Q Chen Wen-You WY Yang Qing-Sheng QS Zhao Jian-Fu JF Qin Yan-Ru YR Xu Li-Yan LY Li En-Min EM Liao Hua-Xin HX Li Bin B He Qing-Yu QY

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20200701 16

Metastasis accounts for 90% of cancer death worldwide, and effective therapeutic strategies are lacking. The aim of this work is to identify the key drivers in tumor metastasis and screen therapeutics for treatment of esophageal squamous cell carcinoma (ESCC). Gene Ontology analysis of The Cancer Genome Atlas (TCGA) gene expression datasets of ESCC patients with or without lympy metastasis identifies that TGF<i>β</i>2 is highly enriched in the pathways essential for tumor metastasis and upregula ...[more]

PMID: 32832354

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Project description:Triple-negative breast cancers (TNBC) tend to become invasive and metastatic at early stages in their development. Despite some treatment successes in early-stage localized TNBC, the rate of distant recurrence remains high, and long-term survival outcomes remain poor. In a search for new therapeutic targets for this disease, we observed that elevated expression of the serine/threonine kinase calcium/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) is highly correlated with tumor invasiveness. In validation studies, genetic disruption of CaMKK2 expression or inhibition of its activity with small molecule inhibitors disrupted spontaneous metastatic outgrowth from primary tumors in murine xenograft models of TNBC. High-grade serous ovarian cancer (HGSOC), a high-risk, poor prognosis ovarian cancer subtype, shares many features with TNBC, and CaMKK2 inhibition effectively blocked metastatic progression in a validated xenograft model of this disease. Mechanistically, CaMKK2 increased the expression of the phosphodiesterase PDE1A, which hydrolyzed cyclic guanosine monophosphate (cGMP) to decrease the cGMP-dependent activity of protein kinase G1 (PKG1). Inhibition of PKG1 resulted in decreased phosphorylation of vasodilator-stimulated phosphoprotein (VASP), which in its hypophosphorylated state binds to and regulates F-actin assembly to facilitate cell movement. Together, these findings establish a targetable CaMKK2-PDE1A-PKG1-VASP signaling pathway that controls cancer cell motility and metastasis by impacting the actin cytoskeleton. Furthermore, it identifies CaMKK2 as a potential therapeutic target that can be exploited to restrict tumor invasiveness in patients diagnosed with early-stage TNBC or localized HGSOC.SignificanceCaMKK2 regulates actin cytoskeletal dynamics to promote tumor invasiveness and can be inhibited to suppress metastasis of breast and ovarian cancer, indicating CaMKK2 inhibition as a therapeutic strategy to arrest disease progression.

Dataset Information

Direct Targeting of CREB1 with Imperatorin Inhibits TGF?2-ERK Signaling to Suppress Esophageal Cancer Metastasis.

Publications

Direct Targeting of CREB1 with Imperatorin Inhibits TGF<i>β</i>2-ERK Signaling to Suppress Esophageal Cancer Metastasis.

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