FGF19/FGFR4 signaling axis confines and switches the role of melatonin in head and neck cancer metastasis

Lang, Liwei; Xiong, Yuanping; Prieto-Domínguez, Néstor; Loveless, Reid; Jensen, Caleb; Shay, Chloe; Teng, Yong

doi:10.1186/s13046-021-01888-9

Cited by 17 publications

(11 citation statements)

References 53 publications

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“…All cell lines were cultured in DMEM medium containing 10% fetal bovine serum at 37 °C in a humidified incubator with 5% CO 2 . Western blotting, plasmid transfection, lentiviral infection, cell proliferation, and colony formation assays were carried out as we previously described [ 7 , 21 , 22 ].…”

Section: Methodsmentioning

confidence: 99%

Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer

Lang

Wang

Ding

et al. 2021

J Exp Clin Cancer Res

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Background Alterations in metabolism are one of the emerging hallmarks of cancer cells and targeting dysregulated cancer metabolism provides a new approach to developing more selective therapeutics. However, insufficient blockade critical metabolic dependencies of cancer allows the development of metabolic bypasses, thus limiting therapeutic benefits. Methods A series of head and neck squamous cell carcinoma (HNSCC) cell lines and animal models were used to determine the efficacy of CPI-613 and CB-839 when given alone or in combination. Glutaminase 1 (GLS1) depletion was achieved by lentiviral shRNAs. Cell viability and apoptosis were determined in HNSCC cells cultured in 2D culture dish and SeedEZ™ 3D scaffold. Molecular alterations were examined by Western blotting and immunohistochemistry. Metabolic changes were assessed by glucose uptake, lactate production, glutathione levels, and oxygen consumption rate. Results We show here that HNSCC cells display strong addiction to glutamine. CPI-613, a novel lipoate analog, redirects cellular activity towards tumor-promoting glutaminolysis, leading to low anticancer efficacy in HNSCC cells. Mechanistically, CPI-613 inhibits the tricarboxylic acid cycle by blocking the enzyme activities of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, which upregulates GLS1 and eventually promotes the compensatory role of glutaminolysis in cancer cell survival. Most importantly, the addition of a GLS1 inhibitor CB-839 to CPI-613 treatment abrogates the metabolic dependency of HNSCC cells on glutamine, achieving a synergistic anticancer effect in glutamine-addicted HNSCC. Conclusions These findings uncover the critical role of GLS1-mediated glutaminolysis in CPI-613 treatment and suggest that the CB-839 and CPI-613 combination may potentiate synergistic anticancer activity for HNSCC therapeutic gain.

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Section: Methodsmentioning

confidence: 99%

Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer

Lang

Wang

Ding

et al. 2021

J Exp Clin Cancer Res

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“…Previous studies revealed melatonin has significant inhibitory effects on numerous cancers [5][6][7][8][9]. Melatonin exerted anticancer actions in almost every stage of tumor generation and development through the joint effect of multiple functions, such as inhibiting proliferation, angiogenesis and metastasis, affecting aerobic metabolism, and enhancing chemotherapy efficiency [5][6][7][8][9][10][11].…”

Section: Discussionmentioning

confidence: 99%

“…Melatonin, a hormone mainly secreted from the pineal gland, has been proven to possess extensive biological activities including circadian rhythms regulation, anti-oxidation, anti-inflammation and immunoregulation [1][2][3][4][5]. As to cancer, mounting evidence indicates that melatonin exhibits oncostatic features at the initiation, progression and metastasis phases through multiple and interrelated mechanisms [5][6][7][8][9][10][11]. Esophageal squamous cell carcinoma (ESCC) is ranked as the 6th leading cause of cancer-related deaths in the world [12,13].…”

Section: Introductionmentioning

confidence: 99%

Melatonin inhibits ESCC tumor growth by mitigating the HDAC7/β-catenin/c-Myc positive feedback loop and suppressing the USP10-maintained HDAC7 protein stability

Feng

Guo

et al. 2022

Military Med Res

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Background Melatonin, a natural hormone secreted by the pineal gland, has been reported to exhibit antitumor properties through diverse mechanisms of action. However, the oncostatic function of melatonin on esophageal squamous cell carcinoma (ESCC) remains elusive. This study was conducted to investigate the potential effect and underlying molecular mechanism of melatonin as single anticancer agent against ESCC cells. Methods ESCC cell lines treated with or without melatonin were used in this study. In vitro colony formation and EdU incorporation assays, and nude mice tumor xenograft model were used to confirm the proliferative capacities of ESCC cells. RNA-seq, qPCR, Western blotting, recombinant lentivirus-mediated target gene overexpression or knockdown, plasmids transfection and co-IP were applied to investigate the underlying molecular mechanism by which melatonin inhibited ESCC cell growth. IHC staining on ESCC tissue microarray and further survival analyses were performed to explore the relationship between target genes’ expression and prognosis of ESCC. Results Melatonin treatment dose-dependently inhibited the proliferative ability and the expression of histone deacetylase 7 (HDAC7), c-Myc and ubiquitin-specific peptidase 10 (USP10) in ESCC cells (P < 0.05). The expressions of HDAC7, c-Myc and USP10 in tumors were detected significantly higher than the paired normal tissues from 148 ESCC patients (P < 0.001). Then, the Kaplan–Meier survival analyses suggested that ESCC patients with high HDAC7, c-Myc or USP10 levels predicted worse overall survival (Log-rank P < 0.001). Co-IP and Western blotting analyses further revealed that HDAC7 physically deacetylated and activated β-catenin thus promoting downstream target c-Myc gene transcription. Notably, our mechanistic study validated that HDAC7/β-catenin/c-Myc could form the positive feedback loop to enhance ESCC cell growth, and USP10 could deubiquitinate and stabilize HDAC7 protein in the ESCC cells. Additionally, we verified that inhibition of the HDAC7/β-catenin/c-Myc axis and USP10/HDAC7 pathway mediated the anti-proliferative action of melatonin on ESCC cells. Conclusions Our findings elucidate that melatonin mitigates the HDAC7/β-catenin/c-Myc positive feedback loop and inhibits the USP10-maintained HDAC7 protein stability thus suppressing ESCC cell growth, and provides the reference for identifying biomarkers and therapeutic targets for ESCC.

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“…Immunohistochemistry (IHC) was performed as previously described ( 21 ). Briefly, paraffin-embedded xenografts or tissues were cut into 3-μm sections and mounted on slides, subjected to antigen retrieval in hot citrate buffer (pH = 7.4), then blocked in 10% normal goat serum.…”

Section: Methodsmentioning

confidence: 99%

Using Patient-Derived Xenografts to Explore the Efficacy of Treating Head-and-Neck Squamous Cell Carcinoma With Anlotinib

Hu¹,

Guo²,

Yu³

et al. 2021

Pathol. Oncol. Res.

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Objective: The efficacy of anlotinib as a treatment for head-and-neck squamous cell carcinoma (HNSCC) has been little explored. Here, we used patient-derived xenografts (PDXs) to this end.Methods: Fresh tumor tissues of HNSCC patients were screened in terms of in vitro drug sensitivity using the MTT assay. Patient PDXs were used to confirm the anti-tumor effects of anlotinib in vivo. After the medication regimen was complete, the tumor volume changes in mice were calculated. Apoptosis was measured using the TUNEL assay. The cell proliferation and apoptosis levels of PDXs yielded data on the utility of anlotinib treatment in vivo.Results: Anlotinib suppressed the in vitro proliferation of nine tumor tissues by an average of 51.05 ± 13.74%. Anlotinib also significantly inhibited the growth of three PDXs in mice (tumor growth inhibition 79.02%). The expression levels of Ki-67 and proliferating cell nuclear antigen after anlotinib treatment were significantly lower than those in the controls. The negative and positive controls exhibited no and some apoptosis, respectively, whereas the anlotinib group evidenced extensive apoptosis.Conclusion: Anlotinib suppressed HNSCC growth in vitro and in vivo (by inhibiting cell proliferation and promoting apoptosis), suggesting that anlotinib can potentially treat HNSCC.

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FGF19/FGFR4 signaling axis confines and switches the role of melatonin in head and neck cancer metastasis

Cited by 17 publications

References 53 publications

Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer

Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer

Melatonin inhibits ESCC tumor growth by mitigating the HDAC7/β-catenin/c-Myc positive feedback loop and suppressing the USP10-maintained HDAC7 protein stability

Using Patient-Derived Xenografts to Explore the Efficacy of Treating Head-and-Neck Squamous Cell Carcinoma With Anlotinib

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