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1.
Cancer Res ; 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34580061

RESUMO

Tumor-initiating cells (TIC) are associated with tumor initiation, growth, metastasis, and recurrence. Aldehyde dehydrogenase 1A1 (ALDH1A1) is a TIC marker in many cancers, including breast cancer. However the molecular mechanisms underlying ALDH1A1 functions in solid tumors remain largely unknown. Here we demonstrate that ALDH1A1 enzymatic activity facilitates breast tumor growth. Mechanistically, ALDH1A1 decreased the intracellular pH in breast cancer cells to promote phosphorylation of TAK1, activate NFκB signaling, and increase the secretion of granulocyte macrophage colony-stimulating factor (GM-CSF), which led to myeloid-derived suppressor cell (MDSC) expansion and immunosuppression. Furthermore, the ALDH1A1 inhibitor disulfiram and chemotherapeutic agent gemcitabine cooperatively inhibited breast tumor growth and tumorigenesis by purging ALDH+ TICs and activating T cell immunity. These findings elucidate how active ALDH1A1 modulates the immune system to promote tumor development, highlghting new therapeutic strategies for malignant breast cancer.

2.
Nat Commun ; 12(1): 4413, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285210

RESUMO

Enhanced neovasculogenesis, especially vasculogenic mimicry (VM), contributes to the development of triple-negative breast cancer (TNBC). Breast tumor-initiating cells (BTICs) are involved in forming VM; however, the specific VM-forming BTIC population and the regulatory mechanisms remain undefined. We find that tumor endothelial marker 8 (TEM8) is abundantly expressed in TNBC and serves as a marker for VM-forming BTICs. Mechanistically, TEM8 increases active RhoC level and induces ROCK1-mediated phosphorylation of SMAD5, in a cascade essential for promoting stemness and VM capacity of breast cancer cells. ASB10, an estrogen receptor ERα trans-activated E3 ligase, ubiquitylates TEM8 for degradation, and its deficiency in TNBC resulted in a high homeostatic level of TEM8. In this work, we identify TEM8 as a functional marker for VM-forming BTICs in TNBC, providing a target for the development of effective therapies against TNBC targeting both BTIC self-renewal and neovasculogenesis simultaneously.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas dos Microfilamentos/metabolismo , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/patologia , Receptores de Superfície Celular/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Mama/patologia , Mama/cirurgia , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Linhagem Celular Tumoral , Autorrenovação Celular/efeitos dos fármacos , Feminino , Humanos , Mastectomia , Camundongos , Proteínas dos Microfilamentos/antagonistas & inibidores , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Receptores de Superfície Celular/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/irrigação sanguínea , Neoplasias de Mama Triplo Negativas/terapia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Adv Sci (Weinh) ; 7(1): 1901728, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31921558

RESUMO

Breast tumor initiating cells (BTICs) with ALDH+CD24-CD44+ phenotype are the most tumorigenic and invasive cell population in breast cancer. However, the molecular mechanisms are still unclear. Here, it is found that a negative immune regulator interleukin-1 receptor type 2 (IL1R2) is upregulated in breast cancer (BC) tissues and especially in BTICs. BC patients with high IL1R2 expression have a poorer overall survival and relapse-free survival. High IL1R2 promotes BTIC self-renewal and BC cell proliferation and invasion. Mechanistically, IL1R2 is activated by IL1ß, as demonstrated by the fact that IL1ß induces the release of IL1R2 intracellular domain (icd-IL1R2) and icd-IL1R2 then interacts with the deubiquitinase USP15 at the UBL2 domain and promotes its activity, which finally induces BMI1 deubiquitination at lysine 81 and stabilizes BMI1 protein. In addition, IL1R2 neutralizing antibody can suppress the protein expression of both IL1R2 and BMI1, and significantly abrogates the promoting effect of IL1R2 on BTIC self-renewal and BC cell growth both in vitro and in vivo. The current results indicate that blocking IL1R2 with neutralizing antibody provides a therapeutic approach to inhibit BC progression by targeting BTICs.

4.
Cell Death Dis ; 9(12): 1143, 2018 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-30446635

RESUMO

Myristoylation is one of key post-translational modifications that involved in signal transduction, cellular transformation and tumorigenesis. Increasing evidence demonstrates that targeting myristoylation might provide a new strategy for eliminating cancers. However, the underlying mechanisms are still yielded unclear. In this study, we demonstrated that genetic inhibition of N-myristoyltransferase NMT1 suppressed initiation, proliferation and invasion of breast cancer cells either in vitro or in vivo. We identified ROS could negatively regulate NMT1 expression and NMT1 knockdown conversely promoted oxidative stress, which formed a feedback loop. Furthermore, inhibition of NMT1 caused degraded proteins increase and ER stress, which cross-talked with mitochondria to produce more ROS. And both of oxidative stress and ER stress could activate JNK pathway, leading to autophagy which abrogated breast cancer progression especially triple-negative breast cancer (TNBC). These studies provide a preclinical proof of concept for targeting NMT1 as a strategy to treat breast cancer.


Assuntos
Aciltransferases/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácido Mirístico/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Estresse do Retículo Endoplasmático/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Int J Clin Exp Pathol ; 7(7): 4120-7, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25120791

RESUMO

Regulator of G-protein signaling 6 (RGS6), a member of a family of RGS proteins, has been reported to involve in multiple processes during tumor development. However, its role in pancreatic cancer has not been studied yet. In this study, we aimed to investigate the expression of RGS6 in pancreatic cancer and its role in predicting outcomes of patients with pancreatic cancer. We first measured the expression of RGS6 mRNA in 20 cases of tumor tissues and matched adjacent non-tumorous tissues by quantitative real-time PCR and examined RGS6 protein by immunohistochemistry in tissue microarrays containing 90 tumor and 90 paired adjacent non-tumor tissues. Decreased RGS6 mRNA detected in primary tumor, compared with their non-tumor counterparts. In addition, decreased RGS6 protein expression was associated with tumor differentiation (P = 0.027), pT classification (P = 0.034), smoking status (P = 0.041) and a poor survival (P = 0.007). Cox proportional hazards regression modeling analysis revealed that lymph node metastasis (P = 0.001; hazard ratio, 2.347, 95% CI, 1.387-3.972), tumor differentiation (P = 0.015; hazard ratio, 0.505, 95% CI, 0.291-0.876) and RGS6 expression (P = 0.048; hazard ratio, 0.567, 95% CI, 0.324-0.994) were three independent prognostic factors. Taken together, these date demonstrate that RGS6 decreases in tumor tissue and may serve as a novel biomarker for outcomes in pancreatic cancer patients and be a potential therapeutic target potential therapeutic target.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/análise , Neoplasias Pancreáticas/patologia , Proteínas RGS/biossíntese , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Idoso , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Proteínas RGS/análise , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise Serial de Tecidos
6.
Tumour Biol ; 35(10): 9759-67, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24972969

RESUMO

Targeted therapy based on ALK tyrosine kinase inhibitors (ALK-TKIs) has made significant achievements in individuals with EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) fusion positive nonsmall-cell lung cancer (NSCLC). However, a high fraction of patients receive inferior clinical response to such treatment in the initial therapy, and the exact mechanisms underlying this process need to be further investigated. In this study, we revealed a persistently activated PI3K/AKT signaling that mediates the drug ineffectiveness. We found that genetic or pharmacological inhibition of ALK markedly abrogated phosphorylated STAT3 and ERK, but it failed to suppress AKT activity or induce apoptosis, in EML4-ALK-positive H2228 cells. Furthermore, targeted RNA interference of PI3K pathway components restored sensitivity to TAE684 treatment at least partially due to increased apoptosis. Combined TAE684 with PI3K inhibitor synergistically inhibited the proliferation of EML4-ALK-positive cells in vitro and significantly suppressed the growth of H2228 xenografts in vivo, suggesting the potential clinical application of such combinatorial therapy regimens in patients with EML4-ALK positive lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias Pulmonares/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Quinase do Linfoma Anaplásico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Immunoblotting , Neoplasias Pulmonares/genética , Camundongos , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Pirimidinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
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