RESUMEN
BACKGROUND/AIM: Breast cancer is the most predominant type of cancer affecting women worldwide and the current therapeutic treatment for breast cancer patients is not adequately effective. This study aimed to investigate the mechanism of 17-AAG, a heat shock protein (HSP90) inhibitor, as a treatment for inducing breast cancer cell apoptosis. MATERIALS AND METHODS: The pharmacology network was employed to examine the correlation of 17-AAG with the gene expression profiles of breast cancer, obtained by Gene Expression Profiling Interactive Analysis (GEPIA). MTT and flow cytometry were utilized to investigate cell proliferation and cell apoptosis, respectively. Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay and western blot analysis were employed to examine the correlation between cellular oxidant levels and protein expression. Immunofluorescence staining was utilized to confirm the protein localization and assess DNA damage. RESULTS: The pharmacological network analysis revealed that HSP90 serves as the common target connecting 17-AAG and breast cancer genes. Treatment with 17-AAG significantly increased cell apoptosis. Moreover, the treatment resulted in up-regulation of cellular oxidant levels and PERK/eIF2α expression. In line with these, protein localization after treatment revealed an increase in DNA damage, correlating with higher ER stress levels. Furthermore, GEPIA demonstrated that PERK and eIF2α expression were significantly higher in breast invasive carcinoma compared to other tumor types. CONCLUSION: HSP90 emerges as a potential target for inducing apoptosis in breast cancer cells by disrupting protein homeostasis in the endoplasmic reticulum, possibly through PERK/eIF2α up-regulation. 17-AAG, an HSP90 inhibitor, may therefore potentially hold an alternative therapeutic strategy for breast cancer treatment.
Asunto(s)
Apoptosis , Benzoquinonas , Neoplasias de la Mama , Estrés del Retículo Endoplásmico , Factor 2 Eucariótico de Iniciación , Lactamas Macrocíclicas , eIF-2 Quinasa , Humanos , Benzoquinonas/farmacología , Lactamas Macrocíclicas/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Femenino , Estrés del Retículo Endoplásmico/efectos de los fármacos , Factor 2 Eucariótico de Iniciación/metabolismo , Factor 2 Eucariótico de Iniciación/genética , eIF-2 Quinasa/metabolismo , eIF-2 Quinasa/genética , Línea Celular Tumoral , Proteínas HSP90 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/genética , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
[This corrects the article DOI: 10.1371/journal.pone.0302662.].
RESUMEN
Kaab Dum, a prominent indigenous rice variety cultivated in the Pak Phanang Basin of Nakhon Si Thammarat, Thailand, is the focus of our study. We investigate the therapeutic potential of indigenous Kaab Dum rice extract in the context of chronic wounds. Our research encompasses an examination of the nutritional compositions and chemical profiles of Kaab Dum rice extract. Additionally, we assess how the extract affects chronic wounds in TGF-ß-induced HaCaT cells. Our evaluation methods include the detection of cellular oxidative stress, the examination of endoplasmic reticulum (ER) stress, wound healing assays, analysis of cell cycle arrest and the study of cellular senescence through senescence-associated ß-galactosidase (SA-ß-gal) staining. Our research findings demonstrate that TGF-ß induces oxidative stress in HaCaT cells, which subsequently triggers ER stress, confirmed by the expression of the PERK protein. This ER stress results in cell cycle arrest in HaCaT cells, characterized by an increase in p21 protein, a cyclin-dependent kinase inhibitor (CDKI). Ultimately, this leads to cellular senescence, as confirmed by SA-ß-gal staining. Importantly, our study reveals the effectiveness of Kaab Dum rice extract in promoting wound healing in the chronic wound model. The extract reduces ER stress and senescent cells. These beneficial effects are potentially linked to the antioxidant and anti-inflammatory properties of the rice extract. The findings of our study have the potential to make significant contributions to the development of enhanced products for both the prevention and treatment of chronic wounds.
Asunto(s)
Senescencia Celular , Estrés del Retículo Endoplásmico , Queratinocitos , Oryza , Extractos Vegetales , Cicatrización de Heridas , Humanos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular , Senescencia Celular/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Células HaCaT , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Oryza/química , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Tailandia , Factor de Crecimiento Transformador beta/metabolismo , Cicatrización de Heridas/efectos de los fármacosRESUMEN
BACKGROUND/AIM: Breast cancer is the most prevalent form of cancer among women worldwide, with a high mortality rate. While the most common cause of breast cancer death is metastasis, there is currently no potential treatment for patients at the metastatic stage. The present study investigated the potential of using a combination of HSP90 and mTOR inhibitor in the treatment of breast cancer cell growth, migration, and invasion. MATERIALS AND METHODS: Gene Expression Profiling Interactive Analysis (GEPIA) was used to investigate the gene expression profiles. Western blot analysis and fluorescence staining were used for protein expression and localization, respectively. MTT, wound healing, and transwell invasion assays were used for cell proliferation, migration, and invasion, respectively. RESULTS: GEPIA demonstrated that HSP90 expression was significantly higher in breast invasive carcinoma compared to other tumor types, and this expression correlated with mTOR levels. Treatment with 17-AAG, an HSP90 inhibitor, and Torkinib, an mTORC1/2 inhibitor, significantly inhibited cell proliferation. Moreover, combination treatment led to down-regulation of AKT. Morphological changes revealed a reduction in F-actin intensity, a marked reduction of YAP, with interference in nuclear localization. CONCLUSION: Targeting HSP90 and mTOR has the potential to suppress breast cancer cell growth and progression by disrupting AKT signaling and inhibiting F-actin polymerization. This combination treatment may hold promise as a therapeutic strategy for breast cancer treatment that ameliorates adverse effects of a single treatment.