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1.
Cell Death Dis ; 15(5): 319, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38710705

RESUMO

Argininosuccinate synthase (ASS1), a critical enzyme in the urea cycle, acts as a tumor suppressor in many cancers. To date, the anticancer mechanism of ASS1 has not been fully elucidated. Here, we found that phosphoglycerate dehydrogenase (PHGDH), a key rate-limiting enzyme in serine synthesis, is a pivotal protein that interacts with ASS1. Our results showed that ASS1 directly binds to PHGDH and promotes its ubiquitination-mediated degradation to inhibit serine synthesis, consequently suppressing tumorigenesis. Importantly, the tumor suppressive effects of ASS1 were strongly abrogated by PHGDH knockout. In addition, ASS1 knockout and knockdown partially rescued cell proliferation when serine and glycine were depleted, while the inhibitory effect of ASS1 overexpression on cell proliferation was restored by the addition of serine and glycine. These findings unveil a novel role of ASS1 and suggest that the ASS1/PHGDH serine synthesis pathway is a promising target for cancer therapy.


Assuntos
Argininossuccinato Sintase , Proliferação de Células , Fosfoglicerato Desidrogenase , Serina , Neoplasias de Mama Triplo Negativas , Fosfoglicerato Desidrogenase/metabolismo , Fosfoglicerato Desidrogenase/genética , Serina/metabolismo , Serina/biossíntese , Humanos , Feminino , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/genética , Animais , Argininossuccinato Sintase/metabolismo , Argininossuccinato Sintase/genética , Linhagem Celular Tumoral , Camundongos Nus , Ubiquitinação , Camundongos , Glicina/metabolismo
2.
J Nat Prod ; 86(9): 2111-2121, 2023 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-37682035

RESUMO

Spinosyn A (SPA), derived from a soil microorganism, Saccharopolyspora spinosa, and its derivative, LM2I, has potential inhibitory effects on a variety of cancer cells. However, the effects of SPA and LM2I in inhibiting the growth of human colorectal cancer cells and the molecular mechanisms underlying these effects are not fully understood. Cell viability was tested by using a 3-(4,5-dimethylthiazol-2-yl-)-2,5-diphenyltetrazolium bromide (MTT) assay and a colony formation assay. On the basis of the IC50 values of SPA and LM2I in seven colorectal cancer (CRC) cell lines, sensitive (HT29 and SW480) and insensitive (SW620 and RKO) cell lines were screened. The GSE2509 and GSE10843 data sets were used to identify 69 differentially expressed genes (DEGs) between sensitive and insensitive cell lines. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and protein-protein interactions (PPI) were performed to elucidate the molecular mechanisms of the DEGs. The hub gene of the DEGs was detected by Western blot analysis and verified using the CRISPR/Cas9 system. Our data indicate that SPA and its derivative LM2I have significant antiproliferative activity in seven colorectal cancer cell lines and colorectal xenograft tumors. On the basis of bioinformatics analysis, it was demonstrated that epidermal growth factor receptor (EGFR) was the hub gene of the DEGs and was associated with the inhibitory effects of SPA and LM2I in CRC cell lines. The study also revealed that SPA and LM2I inhibited the EGFR pathway in vitro and in vivo.


Assuntos
Neoplasias Colorretais , Macrolídeos , Humanos , Receptores ErbB , Bioensaio , Neoplasias Colorretais/tratamento farmacológico
3.
Cancers (Basel) ; 15(9)2023 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-37173892

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with shorter five-year survival than other breast cancer subtypes, and lacks targeted and hormonal treatment strategies. The signal transducer and activator of transcription 3 (STAT3) signaling is up-regulated in various tumors, including TNBC, and plays a vital role in regulating the expression of multiple proliferation- and apoptosis-related genes. RESULTS: By combining the unique structures of the natural compounds STA-21 and Aulosirazole with antitumor activities, we synthesized a class of novel isoxazoloquinone derivatives and showed that one of these compounds, ZSW, binds to the SH2 domain of STAT3, leading to decreased STAT3 expression and activation in TNBC cells. Furthermore, ZSW promotes STAT3 ubiquitination, inhibits the proliferation of TNBC cells in vitro, and attenuates tumor growth with manageable toxicities in vivo. ZSW also decreases the mammosphere formation of breast cancer stem cells (BCSCs) by inhibiting STAT3. CONCLUSIONS: We conclude that the novel isoxazoloquinone ZSW may be developed as a cancer therapeutic because it targets STAT3, thereby inhibiting the stemness of cancer cells.

4.
Nat Commun ; 12(1): 2263, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859183

RESUMO

Argininosuccinate synthase (ASS1) is a ubiquitous enzyme in mammals that catalyzes the formation of argininosuccinate from citrulline and aspartate. ASS1 genetic deficiency in patients leads to an autosomal recessive urea cycle disorder citrullinemia, while its somatic silence or down-regulation is very common in various human cancers. Here, we show that ASS1 functions as a tumor suppressor in breast cancer, and the pesticide spinosyn A (SPA) and its derivative LM-2I suppress breast tumor cell proliferation and growth by binding to and activating ASS1. The C13-C14 double bond in SPA and LM-2I while the Cys97 (C97) site in ASS1 are critical for the interaction between ASS1 and SPA or LM-2I. SPA and LM-2I treatment results in significant enhancement of ASS1 enzymatic activity in breast cancer cells, particularly in those cancer cells with low ASS1 expression, leading to reduced pyrimidine synthesis and consequently the inhibition of cancer cell proliferation. Thus, our results establish spinosyn A and its derivative LM-2I as potent ASS1 enzymatic activator and tumor inhibitor, which provides a therapeutic avenue for tumors with low ASS1 expression and for those non-tumor diseases caused by down-regulation of ASS1.


Assuntos
Argininossuccinato Sintase/metabolismo , Neoplasias da Mama/tratamento farmacológico , Citrulinemia/tratamento farmacológico , Ativadores de Enzimas/farmacologia , Macrolídeos/farmacologia , Proteínas Supressoras de Tumor/agonistas , Adulto , Idoso , Animais , Argininossuccinato Sintase/genética , Argininossuccinato Sintase/isolamento & purificação , Ácido Aspártico/metabolismo , Mama/patologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citrulina/metabolismo , Citrulinemia/genética , Ativadores de Enzimas/uso terapêutico , Feminino , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Macrolídeos/uso terapêutico , Metabolômica , Camundongos , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Mutação , Ligação Proteica , Pirimidinas/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Control Release ; 269: 405-422, 2018 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29170140

RESUMO

Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths worldwide largely due to lack of effective targeted drugs to simultaneously block multiple cancer-driving pathways. The identification of all-trans retinoic acid (ATRA) as a potent Pin1 inhibitor provides a promising candidate for HCC targeted therapy because Pin1 is overexpressed in most HCC and activates numerous cancer-driving pathways. However, the efficacy of ATRA against solid tumors is limited due to its short half-life of 45min in humans. A slow-releasing ATRA formulation inhibits solid tumors such as HCC, but can be used only in animals. Here, we developed a one-step, cost-effective route to produce a novel biocompatible, biodegradable, and non-toxic controlled release formulation of ATRA for effective HCC therapy. We used supercritical carbon dioxide process to encapsulate ATRA in largely uniform poly L-lactic acid (PLLA) microparticles, with the efficiency of 91.4% and yield of 68.3%, and ~4-fold higher Cmax and AUC over the slow-releasing ATRA formulation. ATRA-PLLA microparticles had good biocompatibility, and significantly enhanced the inhibitory potency of ATRA on HCC cell growth, improving IC50 by over 3-fold. ATRA-PLLA microparticles exerted its efficacy likely through degrading Pin1 and inhibiting multiple Pin1-regulated cancer pathways and cell cycle progression. Indeed, Pin1 knock-down abolished ATRA inhibitory effects on HCC cells and ATRA-PLLA did not inhibit normal liver cells, as expected because ATRA selectively inhibits active Pin1 in cancer cells. Moreover ATRA-PLLA microparticles significantly enhanced the efficacy of ATRA against HCC tumor growth in mice through reducing Pin1, with a better potency than the slow-releasing ATRA formulation, consistent with its improved pharmacokinetic profiles. This study illustrates an effective platform to produce controlled release formulation of anti-cancer drugs, and ATRA-PLLA microparticles might be a promising targeted drug for HCC therapy as PLLA is biocompatible, biodegradable and nontoxic to humans.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Portadores de Fármacos/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Poliésteres/administração & dosagem , Tretinoína/administração & dosagem , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Peptidilprolil Isomerase de Interação com NIMA/antagonistas & inibidores , Poliésteres/química , Poliésteres/farmacocinética , Tretinoína/química , Tretinoína/farmacocinética
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