RESUMEN
The tumor suppressor protein p53 is central to cancer biology, with its pathway reactivation emerging as a promising therapeutic strategy in oncology. This study introduced LZ22, a novel compound that selectively inhibits the growth, migration, and metastasis of tumor cells expressing wild-type p53, demonstrating ineffectiveness in cells devoid of p53 or those expressing mutant p53. LZ22's mechanism of action involves a high-affinity interaction with the histidine-96 pocket of the MDM2 protein. This interaction disrupted the MDM2-p53 binding, consequently stabilizing p53 by shielding it from proteasomal degradation. LZ22 impeded cell cycle progression and diminished cell proliferation by reinstating the p53-dependent suppression of the CDK2/Rb signaling pathway. Moreover, LZ22 alleviated the p53-dependent repression of Snail transcription factor expression and its consequent EMT, effectively reducing tumor cell migration and distal metastasis. Importantly, LZ22 administration in tumor-bearing mice did not manifest notable side effects. The findings position LZ22 as a structurally unique reactivator of p53, offering therapeutic promise for the management of human cancers with wild-type TP53.
Asunto(s)
Factores de Transcripción , Proteína p53 Supresora de Tumor , Ratones , Humanos , Animales , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Línea Celular Tumoral , Proliferación Celular , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transducción de Señal , Quinasa 2 Dependiente de la Ciclina/metabolismoRESUMEN
Selenol is a key metabolite of Na2SeO3 and plays an important role in many physiological and pathological processes. The real-time monitoring of selenol is of scientific interest for understanding the anti-cancer mechanism of Na2SeO3. Based on selenol's ability to specifically break AuS bonds and form more stable AuSe bonds on the surfaces of gold nanoparticles (AuNPs), we developed a novel near-infrared fluorescent nanosensor (Cy5.5-peptide-AuNPs) for detecting selenol. The nanosensor exhibited rapid response to selenol with high selectivity and sensitivity, and it was successfully used to image changes in the selenol level in HepG2 cells during Na2SeO3-induced apoptosis. Moreover, in vivo fluorescence imaging of selenol was obtained from H22 tumor-bearing mice injected with both the nanosensor and sodium selenite. The results showed that the tumor cell apoptosis induced by Na2SeO3 is correlated with high-level of selenol under hypoxic conditions. We believe that this nanosensor could serve as a powerful tool for monitoring selenol and exploring the physiological function of selenol in a variety of physiological and pathological contexts and that the probe-designed strategy will provide a new platform for research on relevant selenium chemistry.