HLJ1 is an endogenous Src inhibitor that suppresses cancer progression through dual mechanisms
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE72715 | GEO | 2018/09/03
REPOSITORIES: GEO
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Project description:The tyrosine kinase Src is involved in the progression of many cancers. Moreover, inhibiting Src activity has been shown to obstruct several signaling pathways regulated by the EGFR. Thus, Src is a valuable target molecule in drug development. The purpose of this study was to identify compounds that directly or indirectly modulate Src to suppress lung cancer cell growth and motility and to investigate the molecular mechanisms underlying the effects of these compounds.Human non-small cell lung cancer (NSCLC) cell lines (PC9, PC9/gef, A549, and H1975) with different EGFR statuses were tested by cytotoxicity and proliferation assays after AC-93253 iodide treatment. Src and Src-related protein expression in AC-93253 iodide-treated PC9, PC9/gef, and A549 cells were assessed by western blotting. The effects of AC-93253 iodide on cancer cell colony formation, invasion, and migration were assessed in PC9 and PC9/gef cells. The synergistic effects of gefitinib and AC-93253 iodide were evaluated by combination index (CI)-isobologram analysis in gefitinib-resistant cell lines. The efficacy of AC-93253 iodide in vivo was determined using nude mice treated with either the compound or the vehicle.Among the compounds, AC-93253 iodide exhibited the most potent dose-independent inhibitory effects on the activity of Src as well as on that of the Src-related proteins EGFR, STAT3, and FAK. Furthermore, AC-93253 iodide significantly suppressed cancer cell proliferation, colony formation, invasion, and migration in vitro and tumor growth in vivo. AC-93253 iodide sensitized tumor cells to gefitinib treatment regardless of whether the cells were gefitinib-sensitive (PC9) or resistant (H1975 and PC9/gef), indicating that it may exert synergistic effects when used in combination with established therapeutic agents. Our findings also suggested that the inhibitory effects of AC-93253 iodide on lung cancer progression may be attributable to its ability to modulate multiple proteins, including Src, PI3K, JNK, Paxillin, p130cas, MEK, ERK, and EGFR.Our data suggest that AC-93253 iodide inhibits NSCLC cell growth and motility by regulating multiple Src-related pathways. Our findings may facilitate the development of therapeutic strategies and anti-tumor drugs that may be useful for treating lung cancer in the future.
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Project description:UM-164 is a dual inhibitor of c-Src and p38 MAPK, and has been a lead compound for targeting triple-negative breast cancer. UM-164 shows stronger binding to the active sites of Src compared with the conventional Src inhibitor Dasatinib. While Dasatinib has displayed some inhibitory effects on glioma growth in clinical trials, whether UM-164 can suppress glioma growth has not been reported. Here we show that UM-164 suppressed the proliferation, migration and spheroid formation of glioma cells, and induced cell cycle arrest in the G1 phase. Moreover, UM-164 triggered YAP translocation to the cytoplasm and reduced the activity of YAP, as evidenced by a luciferase assay. Accordingly, UM-164 markedly decreased the expression levels of YAP target genes CYR61 and AXL. Importantly, ectopic expression of wild-type YAP or YAP-5SA (YAP constitutively active mutant) could rescue the anti-proliferative effect induced by UM-164. Intriguingly, p38 MAPK appears to play a greater role than Src in UM-164-mediated inhibition of YAP activity. Furthermore, the in vitro anti-glioma effect mediated by UM-164 was confirmed in a xenograft glioma model. Together, these findings reveal a mechanism by which UM-164 suppresses the malignant phenotypes of glioma cells and might provide a rationale for UM-164-based anti-glioma clinical trials.
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Project description:BackgroundProlactinoma is the most common type of pituitary tumors, and its resultant tumor occupying and hormone disturbance greatly damage the health of patients. In this study, we investigated a protein kinase-PDZ Binding Kinase (PBK)/T-LAK Cell-Originated Protein Kinase (TOPK) as a candidate protein regulating prolactin (PRL) secretion and tumor growth of prolactinomas.MethodsDownloaded prolactinoma transcriptome dataset from Gene Expression Omnibus (GEO) database, and screened differentially expressed genes (DEGs) between normal pituitary tissues and prolactinoma tissues. Then, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were performed, a protein-protein interaction (PPI) network was constructed and the hub genes were identified. After a literature search, TOPK was presumed as an candidate target regulating the prolactinoma. We found a specific inhibitor of TOPK to investigate its effects on the proliferation, migration, apoptosis and PRL secretion of pituitary tumor cells. Finally, the regulation of TOPK inhibitor on its downstream target-p38 Mitogen Activated Protein Kinase (p38 MAPK) was detected to explore the potential mechanism.ResultsA total of 361 DEGs were identified, and 20 hub genes were screened out. TOPK inhibitor HI-TOPK-032 could suppress the proliferation & migration and induce apoptosis of pituitary tumor cells in vitro, and reduce PRL secretion and tumor growth in vivo. HI-TOPK-032 also inhibited the phosphorylation level of the downstream target p38 MAPK, suggesting that TOPK inhibitors regulate the development of prolactinoma by mediating p38 MAPK.ConclusionOur study of identification and functional validation of TOPK suggests that this candidate can be a promising molecular target for prolactinoma treatment.
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Project description:Protein N-myristoylation enables localization to membranes and helps maintain protein conformation and function. N-myristoyltransferases (NMT) catalyze co- or posttranslational myristoylation of Src family kinases and other oncogenic proteins, thereby regulating their function. In this study, we provide genetic and pharmacologic evidence that inhibiting the N-myristoyltransferase NMT1 suppresses cell-cycle progression, proliferation, and malignant growth of prostate cancer cells. Loss of myristoylation abolished the tumorigenic potential of Src and its synergy with androgen receptor in mediating tumor invasion. We identified the myristoyl-CoA analogue B13 as a small-molecule inhibitor of NMT1 enzymatic activity. B13 exposure blocked Src myristoylation and Src localization to the cytoplasmic membrane, attenuating Src-mediated oncogenic signaling. B13 exerted its anti-invasive and antitumor effects against prostate cancer cells, with minimal toxic side-effects in vivo Structural optimization based on structure-activity relationships enabled the chemical synthesis of LCL204, with enhanced inhibitory potency against NMT1. Collectively, our results offer a preclinical proof of concept for the use of protein myristoylation inhibitors as a strategy to block prostate cancer progression. Cancer Res; 77(24); 6950-62. ©2017 AACR.
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Project description:Dasatinib, a dual Src family kinase and Abl inhibitor, is being tested clinically for the treatment of prostate cancer bone metastasis. Bidirectional interactions between osteoblasts and prostate cancer cells are critical in the progression of prostate cancer in bone, but the effect of dasatinib on osteoblasts is unknown. We found that dasatinib inhibited proliferation of primary mouse osteoblasts isolated from mouse calvaria and the immortalized MC3T3-E1 cell line. In calvarial osteoblasts from Col-luc transgenic mice carrying osteoblast-specific Col1alpha1 promoter reporter, luciferase activity was inhibited. Dasatinib also inhibited fibroblast growth factor-2-induced osteoblast proliferation, but strongly promoted osteoblast differentiation, as reflected by stimulation of alkaline phosphatase activity, osteocalcin secretion and osteoblast mineralization. To determine how dasatinib blocks proliferative signaling in osteoblasts, we analyzed the expression of a panel of tyrosine kinases, including Src, Lyn, Fyn, Yes and Abl, in osteoblasts. In the Src family kinases, only Src was activated at a high level. Abl was expressed at a low level in osteoblasts. Phosphorylation of Src-Y419 or Abl-Y245 was inhibited by dasatinib treatment. Knockdown of either Src or Abl by lenti-shRNA in osteoblasts enhances osteoblast differentiation, suggesting that dasatinib enhances osteoblast differentiation through inhibition of both Src and Abl.
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Project description:The tyrosine kinase Src plays an essential role in the progression of many cancers and is involved in several epidermal growth factor receptor (EGFR)-mediated signalling pathways. To improve the efficacy of lung cancer treatments, this study aimed to identify novel compounds that can disrupt the Src-EGFR interaction and that are less dependent on EGFR status with wild-type and mutations than other compounds. We used the Src pY419 ELISA as the platform to screen a compound library of more than 400 plant-derived active ingredients and identified peruvoside as a candidate Src-EGFR crosstalk inhibitor. The effects of peruvoside were evaluated by western blotting, cell function assays, combination Index (CI)-isobologram analyses and in vivo experiments. Peruvoside significantly suppressed the phosphorylation of Src, EGFR, and signal transducer and activator of transcription 3 (STAT3) in a dose- and time-dependent manner and somewhat suppressed their protein expression. Cell function assays revealed that peruvoside inhibited the proliferation, invasion, migration, and colony formation of lung cancer cells in vitro and tumour growth in vivo. Furthermore, peruvoside sensitized gefitinib-resistant tumour cells (A549, PC9/gef and H1975) to gefitinib treatment, indicating that peruvoside may exert synergistic effects when used in combination with established therapeutic agents. Our data also demonstrated that the inhibitory effects of peruvoside on lung cancer progression might be attributed to its ability to regulate Src, phosphoinositide 3-kinase (PI3K), c-Jun N-terminal kinase (JNK), Paxillin, p130cas, and EGFR. Our findings suggest that peruvoside suppresses non-small-cell lung carcinoma (NSCLC) malignancy by downregulating multiple Src-related pathways and could serve as a potential base molecule for developing new anticancer drugs and therapeutic strategies for lung cancer.
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