Pharmacological inhibition of DUSP6 suppresses gastric cancer growth and metastasis and overcomes cisplatin resistance

Wu, Qi; Liao, Yi Fu; Lü, Yun; Wang, Yun; Lu, Jia; Zeng, Zhao Lei; Huang, Qi; Sheng, Hui; Yun, Jing Ping; Xie, Dan; Ju, Huai-Qiang; Xu, Rui‐Hua

doi:10.1016/j.canlet.2017.10.007

Cited by 76 publications

(72 citation statements)

References 45 publications

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“…4A). These concentrations were similarly effective in leukemia and gastric cancer cell lines (13,14). The iHSC-1l and STS26T MPNST cell lines were less sensitive to BCI (Fig.…”

Section: Dusp Inhibitor Bci Reduces Human Mpnst Cell Growth and Activmentioning

confidence: 76%

“…Thus, decreased expression of DUSP genes and proteins can occur in human cancer, including in tumors from pancreas and lung (9,10). In contrast, DUSPs are upregulated in some leukemia types including pre-B acute lymphoblastic leukemia (ALL) and DUSP1/6 inhibition has antitumor effects in gastric, breast, and leukemia cancer models (11)(12)(13)(14). In these cases, it is believed that DUSPs help tumors adapt to excessively high levels of growth factor signals.…”

Section: Introductionmentioning

confidence: 99%

“…(E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI) is a specific allosteric inhibitor of DUSP1/6 (12,13,21). Recently, in mouse models of leukemia and gastric cancer, BCI was effective in killing tumor cells in vivo (12)(13)(14)21). We hypothesized that inhibiting DUSPs might be selectively toxic to MPNST cells.…”

Section: Introductionmentioning

confidence: 99%

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Targeted Inhibition of the Dual Specificity Phosphatases DUSP1 and DUSP6 Suppress MPNST Growth via JNK

Ramkissoon

Chaney

Milewski

et al. 2019

Clinical Cancer Research

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Purpose: In neurofibromatosis type 1 (NF1) and in highly aggressive malignant peripheral nerve sheath tumors (MPNSTs), constitutively active RAS-GTP and increased MAPK signaling are important in tumorigenesis. Dual specificity phosphatases (DUSPs) are negative regulators of MAPK signaling that dephosphorylate p38, JNK, and ERK in different settings. Although often acting as tumor suppressors, DUSPs may also act as oncogenes, helping tumor cells adapt to high levels of MAPK signaling. We hypothesized that inhibiting DUSPs might be selectively toxic to cells from NF1-driven tumors.Experimental Design: We examined DUSP gene and protein expression in neurofibroma and MPNSTs. We used small hairpin RNA (shRNA) to knock down DUSP1 and DUSP6 to evaluate cell growth, downstream MAPK signaling, and mechanisms of action. We evaluated the DUSP inhibitor, (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI), in MPNST cell lines and in cell-line and patient-derived MPNST xenografts. Results: DUSP1 and DUSP6 are expressed in NF1-deleted tumors. Knockdown of DUSP1 and DUSP6, alone or in combination, reduced MPNST cell growth and led to ERK and JNK hyperactivation increasing downstream TP53 and p-ATM. The DUSP inhibitor, BCI, diminished the survival of NF1-deleted Schwann cells and MPNST cell lines through activation of JNK. In vivo, treatment of an established cellline xenograft or a novel patient-derived xenograft (PDX) of MPNSTs with BCI increased ERK and JNK activation, caused tumor necrosis and fibrosis, and reduced tumor volume in one model. Conclusions: Targeting DUSP1 and DUSP6 genetically or with BCI effectively inhibits MPNST cell growth and promotes cell death, in vitro and in xenograft models. The data support further investigation of DUSP inhibition in MPNSTs.

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“…4A). These concentrations were similarly effective in leukemia and gastric cancer cell lines (13,14). The iHSC-1l and STS26T MPNST cell lines were less sensitive to BCI (Fig.…”

Section: Dusp Inhibitor Bci Reduces Human Mpnst Cell Growth and Activmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

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Targeted Inhibition of the Dual Specificity Phosphatases DUSP1 and DUSP6 Suppress MPNST Growth via JNK

Ramkissoon

Chaney

Milewski

et al. 2019

Clinical Cancer Research

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“…However, some patients are insensitive to CDDP treatment and develop resistance and cause recurrence and metastasis. In addition, high‐dose treatment often causes several side effects, such as nausea, vomiting, myelosuppression, and nephrotoxicity, which limit the therapeutic efficacy of CDDP (Ge et al, ; Wu et al, ). Therefore, it is of great significance to find new combined agents that increase the sensitivity of gastric cancer cells to CDDP.…”

Section: Introductionmentioning

confidence: 99%

[6]‐Gingerol enhances the cisplatin sensitivity of gastric cancer cells through inhibition of proliferation and invasion via PI3K/AKT signaling pathway

Yang

Zha

Luo

et al. 2019

Phytotherapy Research

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Cisplatin‐based chemotherapy is a widely used chemotherapeutic regimen for gastric cancer; however, drug resistance limits its efficacy. [6]‐Gingerol has been found to exhibit anticancer effects. Here, we aim to explore the potential of [6]‐gingerol in combination with cisplatin as a new regimen for gastric cancer. CCK‐8 assay and colony formation assay were used to determine the effect of [6]‐gingerol in combination with cisplatin on cell viability of gastric cancer cells. Flow cytometry was performed to assess cell cycle distribution. Wound‐healing assay and transwell invasion assay were conducted to examine the migration and invasion abilities. Cell cycle and invasion‐related proteins and mRNAs, as well as PI3K/AKT signaling proteins, were assessed by western blotting and quantitative real‐time polymerase chain reaction. Combination of [6]‐gingerol with cisplatin inhibited cell viability and enhanced cell cycle arrest at G1 phase compared with cisplatin alone. The combination treatment inhibited cell migration and invasion ability and decreased cyclin D1, cyclin A2, matrix metalloproteinase‐9, p‐PI3K, AKT, and p‐AKT protein expressions and increased P21 and P27 mRNA levels. Our study demonstrates that [6]‐gingerol enhances the cisplatin sensitivity of gastric cancer cells and that the mechanisms involve G1 phase arrest, migration and invasion suppression via PI3K/AKT signaling pathway.

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“…Human gastric adenocarcinoma cell line (SGC-7901), maintained in the Surgical Laboratory at Guangzhou Medical University, and the MDR variants SGC-7901/5-FU and SGC-7901/DDP were obtained and maintained in laboratory conditions as described previously [16,17]. Wound healing assay Cells were seeded into six-well plates and transfected with the negative control siRNA-NC or siRNA-XLOC_006753 for 36 h. Then, the cells were serum-starved for 22 h and replenished with 10% fetal bovine serum RPMI-1640 medium.…”

Section: Methodsmentioning

confidence: 99%

Long Non-Coding RNA XLOC_006753 Promotes the Development of Multidrug Resistance in Gastric Cancer Cells Through the PI3K/AKT/mTOR Signaling Pathway

Zeng

Liao

Zou

et al. 2018

Cell Physiol Biochem

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Background/Aims: The development of multidrug resistance (MDR), which results in disease recurrence and metastasis, is a crucial obstacle to successful chemotherapy for patients with gastric cancer (GC). Long non-coding RNAs (lncRNAs) have been found to play various roles in cancer. This study aimed to investigate the effect of XLOC_006753 on the development of MDR in GC cells. Methods: The expression levels of XLOC_006753 in GC patients and MDR GC cell lines (SGC-7901/5-FU and SGC-7901/DDP cell line) were assessed by qRT-PCR. Statistical analyses were conducted to determine the relationship between XLOC_006753 expression and clinical features and to assess the prognostic value of XLOC_006753 for overall survival and progression-free survival. Then, a CCK-8 assay was used to detect cell proliferation ability and chemosensitivity. Flow cytometry was used to detect cell cycle and cell apoptosis. A wound-healing assay and transwell assay were used to detect cell migration. The expression of markers for MDR, G1/S transition, epithelial–mesenchymal transition (EMT) and PI3K/ AKT/mTOR signaling pathway were examined by western blot. Results: XLOC_006753 was highly expressed in GC patients and MDR GC cell lines (SGC-7901/5-FU and SGC-7901/DDP cell lines), and its high expression was positively associated with metastasis, TNM stage, tumor size, and poor survival in GC patients. Moreover, XLOC_006753 was an independent prognostic biomarker of overall survival and progression-free survival for gastric cancer patients. Knocking down XLOC_006753 in the two MDR GC cell lines significantly inhibited cell proliferation, cell viability, cell cycle G1/S transition, and migration. XLOC_006753 knockdown also promoted apoptosis. Furthermore, western blots showed that XLOC_006753 knockdown decreased some markers of MDR, G1/S transition, and EMT expression, while increasing caspase9 expression and inhibiting the PI3K/AKT/mTOR signaling pathway in SGC-7901/5-FU and SGC-7901/DDP cells. Conclusion: High expression of XLOC_006753 promoted the development of MDR, which was activated by the PI3K/AKT/mTOR pathway in GC cells.

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Pharmacological inhibition of DUSP6 suppresses gastric cancer growth and metastasis and overcomes cisplatin resistance

Cited by 76 publications

References 45 publications

Targeted Inhibition of the Dual Specificity Phosphatases DUSP1 and DUSP6 Suppress MPNST Growth via JNK

Targeted Inhibition of the Dual Specificity Phosphatases DUSP1 and DUSP6 Suppress MPNST Growth via JNK

[6]‐Gingerol enhances the cisplatin sensitivity of gastric cancer cells through inhibition of proliferation and invasion via PI3K/AKT signaling pathway

Long Non-Coding RNA XLOC_006753 Promotes the Development of Multidrug Resistance in Gastric Cancer Cells Through the PI3K/AKT/mTOR Signaling Pathway

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