ABSTRACT
Marsdenia tenacissima injection, a standard Marsdenia tenacissima extract (MTE), has been approved as an adjuvant therapeutic agent for various cancers. Our previous study showed that MTE inhibited the proliferation and metastasis of prostate cancer (PCa) cells. However, the underlying mechanisms and active ingredients of MTE against PCa were not completely understood. This study revealed that MTE induced significant decreases in cell viability and clonal growth in PCa cells. In addition, MTE induced the apoptosis of DU145 cells by reducing the mitochondrial membrane potential and increasing the expression of Cleaved Caspase 3/7, Cyt c, and Bax. In vivo, DU145 xenografted NOD-SCID mice treated with MTE showed significantly decreased tumor size. TUNEL staining and Western blot confirmed the pro-apoptotic effects of MTE. Network pharmacology analysis collected 196 ingredients of MTE linked to 655 potential targets, and 709 PCa-associated targets were retrieved, from which 149 overlapped targets were screened out. Pathway enrichment analysis showed that the HIF-1, PI3K-AKT, and ErbB signaling pathways were closely related to tumor apoptosis. Western blot results confirmed that MTE increased the expression of p-AKTSer473 and p-GSK3βSer9, and decreased the expression of p-STAT3Tyr705in vitro and in vivo. A total of 13 compounds in MTE were identified by HPLC-CAD-QTOF-MS/MS and UPLC-QTOF-MS/MS. Molecular docking analysis indicated that six compounds may interact with AKT, GSK3β, and STAT3. In conclusion, MTE induces the endogenous mitochondrial apoptosis of PCa by regulating the AKT/GSK3β/STAT3 signaling axis, resulting in inhibition of PCa growth in vitro and in vivo.
Subject(s)
Mice , Animals , Male , Humans , Mice, Inbred NOD , Mice, SCID , Marsdenia , Proto-Oncogene Proteins c-akt , Glycogen Synthase Kinase 3 beta , Molecular Docking Simulation , Phosphatidylinositol 3-Kinases , Tandem Mass Spectrometry , Prostatic Neoplasms , Apoptosis , STAT3 Transcription FactorABSTRACT
Cytokeratin 1 4 (CK1 4)has a different degree of expression in NSCLC,breast cancer,cer-vical cancer,esophageal cancer and other tumors,except in the normal basal cells.CK1 4 is mainly expressed in the peripheral part of the tumor,which is rarely expressed in the non-aggressive part.Usually the higher malignant of the tumor has the more expression of CK1 4.Given all that,CK1 4 gene plays an important role in the tumor progression and metastasis in a variety of tumors,which can be considered as an biomarker being used in the diagnosis,treatment and prognosis evaluation.