RESUMO
The cancer-associated alternative splicing (AS) events generate cancer-related transcripts which are involved in uncontrolled cell proliferation and drug resistance. However, the key AS variants implicated in tamoxifen (TAM) resistance in breast cancer remain elusive. In the current study, we investigated the landscape of AS events in nine pairs of primary and relapse breast tumors from patients receiving TAM-based therapy. We unrevealed a notable association between the inclusion of exon 7.2 in the 5'untranslated region (5'UTR) of ALDOA mRNA and TAM resistance. Mechanistically, the inclusion of ALDOA exon 7.2 enhances the translation efficiency of the transcript, resulting in increased ALDOA protein expression, mTOR pathway activity, and the promotion of TAM resistance in breast cancer cells. Moreover, the inclusion of exon 7.2 in ALDOA mRNA is mediated by MSI1 via direct interaction. In addition, elevated inclusion of ALDOA exon 7.2 or expression of MSI1 is associated with an unfavorable prognosis in patients undergoing endocrine therapy. Notably, treatment with Aldometanib, an ALDOA inhibitor, effectively restrains the growth of TAM-resistant breast cancer cells in vitro and in vivo. The present study unveils the pivotal role of an AS event in ALDOA, under the regulation of MSI1, in driving TAM resistance in breast cancer. Therefore, this study provides a promising therapeutic avenue targeting ALDOA to combat TAM resistance.
RESUMO
BACKGROUND: Lysine-specific demethylase 1 (LSD1) is highly expressed in a variety of malignant tumors, rendering it a crucial epigenetic target for anti-tumor therapy. Therefore, the inhibition of LSD1 activity has emerged as a promising innovative therapeutic approach for targeted cancer treatment. METHODS: In our study, we employed innovative structure-based drug design methods to meticulously select compounds from the ZINC15 database. Utilizing virtual docking, we evaluated docking scores and binding modes to identify potential inhibitors. To further validate our findings, we harnessed molecular dynamic simulations and conducted meticulous biochemical experiments to deeply analyze the binding interactions between the protein and compounds. RESULTS: Our results showcased that ZINC10039815 exhibits an exquisite binding mode with LSD1, fitting perfectly into the active pocket and forming robust interactions with multiple critical residues of the protein. CONCLUSIONS: With its significant inhibitory effect on LSD1 activity, ZINC10039815 emerges as a highly promising candidate for the development of novel LSD1 inhibitors.
Assuntos
Inibidores Enzimáticos , Histona Desmetilases , Simulação de Acoplamento Molecular , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/metabolismo , Histona Desmetilases/química , Humanos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Simulação de Dinâmica Molecular , Antineoplásicos/farmacologia , Antineoplásicos/química , Desenho de Fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
Environmental exposure to arsenite (As+3) is known to induce immunotoxicity. Natural killer (NK) cells are innate lymphoid cells act as professional killers of tumor cells. Our previous report indicated that 500 ppb As+3 drinking water exposure induced significant DNA damage in the NK cells of C57BL/6 mice. Myricetin is a plant-derived flavonoid known as a strong antioxidant. In this study, daily administration of myricetin at 20 mg/kg was found to alleviate the cell population decrease and DNA damage in the NK cells of BALB/c mice exposed to 500 and 1000 ppb As+3 via drinking water. Oxidative stress and poly(ADP-ribose) polymerase 1 (PARP-1) inhibition were induced by As+3 at 1 and 2 µM in isolated mouse NK cells in vitro, which were attenuated by 20 µM myricetin. The mitigatory effect of myricetin on the PARP-1 inhibition in NK cells treated with As+3 was also found to be the result of its prevention of the zinc loss induced by As+3 on PARP-1. Collectively, these results demonstrated, for the first time, that myricetin could protect NK cells from As+3 induced DNA through attenuating oxidative stress and retaining PARP-1 activity, indicating that myricetin may be utilized for the prevention of the immunotoxicity induced by As+3 in NK cells.