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


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.

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


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.

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
Cell Biol Toxicol ; 37(2): 277-291, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32472219


Uncoupling protein 1 (UCP1) has been implicated in ameliorating metabolic related disorders, of which most symptoms are risk factors for breast cancer. Here, we found that UCP1 was obviously downregulated in basal-like breast cancer (BLBC) and was positively correlated with improved survival. However, the underlying regulatory mechanisms remain largely unknown. Our studies showed that UCP1 inhibited tumor progression via suppressing aldehyde dehydrogenase (ALDH)-positive breast cancer stem cell (BCSC) population in BLBC. Furthermore, we found that UCP1 induced the upregulation of fructose bisphosphatase 1 (FBP1) which was previously blocked by Snail overexpression, and UCP1 decreased ALDH-positive BCSCs via FBP1-dependent metabolic rewiring, which could be reversed by Snail overexpression. In addition, breast cancer cells co-cultured with UCP1-deficient adipocytes had increased proportion of ALDH-positive BCSCs, indicating a potential protection role of UCP1 in tumor microenvironment. These results suggested that UCP1 suppressed BCSCs through inhibiting Snail-mediated repression of FBP1, and that upregulation of UCP1 might be a previously undescribed therapeutic strategy for combating breast cancer. Graphical abstract.

Cell Biol Toxicol ; 35(2): 161-177, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30220009


Aldehyde dehydrogenases (ALDHs) defend intracellular homeostasis by catalyzing the conversion of toxic aldehydes into non-toxic carboxylic acids, which is of particular importance to the self-renewal of stem cells and cancer stem cells. The widely used ALDEFLUOR assay was initially designed to indicate the activity of ALDH1A1 in leukemia and has been demonstrated to detect the enzyme activity of several other ALDH isoforms in various cancer types in recent years. However, it is still elusive which isoforms, among the 19 ALDH isoforms in human genome, are the potential contributors in catalyzing ALDEFLUOR assay in different cancers. In the current study, we performed a screening via overexpressing each ALDH isoform to assess their ability of catalyzing ALDEFLUOR assay. Our results demonstrate that nine isoforms are active in ALDEFLUOR assay, whose overexpression significantly increases ALDH-positive (ALDH+) population. Further analysis of the expression of these active isoforms in various cancers reveals cancer-type specific expression patterns, suggesting that different cancer types may exhibit ALDEFLUOR activity through expression of specific active ALDH isoforms. This study strongly indicates that a detailed elucidation of the functions for each active ALDH isoform in CSCs is necessary and important for a profound understanding of the underlying mechanisms of ALDH-associated stemness.

Aldeído Desidrogenase/genética , Isoenzimas/genética , Neoplasias/enzimologia , Linhagem Celular , Perfilação da Expressão Gênica , Genoma Humano , Células HEK293 , Humanos , Técnicas Imunoenzimáticas , Neoplasias/genética , Células-Tronco Neoplásicas/enzimologia