RESUMEN

BACKGROUND: Mitochondrial homeostasis has been increasingly viewed as a potential target of cancer therapy, and mitochondrial fission is a novel regulator of mitochondrial function and apoptosis. The aim of our study was to determine the detailed role of mitochondrial fission in SW837 colorectal cancer cell viability, mobility and proliferation. In addition, the current study also investigated the therapeutic impact of Tanshinone IIA (Tan IIA), a type of anticancer adjuvant drug, on cancer mitochondrial homeostasis. RESULTS: The results of our data illustrated that Tan IIA promoted SW837 cell death, impaired cell migration and mediated cancer proliferation arrest in a dose-dependent manner. Functional investigation exhibited that Tan IIA treatment evoked mitochondrial injury, as witnessed by mitochondrial ROS overproduction, mitochondrial potential collapse, antioxidant factor downregulation, mitochondrial pro-apoptotic protein upregulation, and caspase-9-dependent apoptotic pathway activation. Furthermore, we confirmed that Tan IIA mediated mitochondrial damage by activating mitochondrial fission, and the inhibition of mitochondrial fission abrogated the proapoptotic effects of Tan IIA on SW837 cells. To this end, our results demonstrated that Tan IIA modulated mitochondrial fission via the JNK-Mff pathways. The blockade of the JNK-Mff axis inhibited Tan IIA-mediated mitochondrial fission and promoted the survival of SW837 cells. CONCLUSIONS: Altogether, our results identified mitochondrial fission as a new potential target to control cancer viability, mobility and proliferation. Furthermore, our findings demonstrate that Tan IIA is an effective drug to treat colorectal cancer by activating JNK-Mff-mitochondrial fission pathways.

Asunto(s)

Abietanos/farmacología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Dinámicas Mitocondriales/efectos de los fármacos , Proteínas Mitocondriales/metabolismo , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología

RESUMEN

Objective To observe the effects of acupuncture on the behaviors and the expressions of Fis1 and OPA1, as well as mitochondrial ultrastructure in the hippocampus of mice with Alzheimer disease (AD); To explore the mechanism of action of acupuncture for AD.Methods Forty male SAMP8 mice were randomly divided into acupuncture group and model group, with 20 mice in each group. Another 20 male natural aging mice with the same age (SAMR1 mice) were set as the normal group. Acupuncture group chose Shenshu, Baihui, Xuehai and Geshu for intervention. 8 weeks later, Morris water maze was used to test the mice behaviors, and then hippocampus organization was taken. Western blot was used to detect the expressions of Fis1 and OPA1 and mitochondrial ultrastructure in hippocampal neurons of mice was observed by transmission electron microscopy.Results Compared with the model group, the escape latency of acupuncture group was significantly shortened (P<0.05), and the stay time in the former platform quadrant and former platform crossing times were significantly increased (P<0.05). The expression of Fis1 in the hippocampus of acupuncture group decreased significantly (P<0.05), while the expression of OPA1 increased significantly (P<0.05). The mitochondrial ultrastructure in hippocampus in the acupuncture group was effectively improved, and the mitochondrial surface density and body density were both increased in the acupuncture group compared with the model group (P<0.05).Conclusion Acupuncture may play a potential therapeutic role in AD by decreasing the expression of Fis1, increasing the expression of OPA1, recovering the injury of mitochondrial ultrastructure.