Dataset Information

Solamargine Inhibits Prostate Cancer Cell Growth and Enhances the Therapeutic Efficacy of Docetaxel via Akt Signaling.

ABSTRACT: Prostate cancer (PCa) has become a leading cause of cancer-associated incidence and mortality in men worldwide. However, most primary PCas relapse to castration-resistant PCa (CRPC) after androgen deprivation treatment. The current treatment for CRPC is based on chemotherapeutic drugs such as docetaxel, while the development of chemoresistance and severe side effects limit the therapeutic benefit. Solamargine, a natural alkaloid isolated from a traditional Chinese herbal medicine known as Solanum nigrum, exhibits antitumor activity in various human cancers. In this study, we demonstrated that solamargine substantially inhibited CRPC cell growth in a dose-dependent manner through the suppression of phosphoinositide 3-kinase (PI3K)/Akt signaling. Moreover, solamargine exhibited significant antitumor effects in mouse xenograft models. Bioinformatics analysis of docetaxel-resistant PCa cells indicated that the PI3K/Akt pathway mediated the chemoresistance of CRPC. Furthermore, solamargine significantly enhanced the efficacy of docetaxel in PCa cells. These results reveal the therapeutic potential of solamargine against human PCa.

SUBMITTER: Ge J

PROVIDER: S-EPMC8930254 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Solamargine Inhibits Prostate Cancer Cell Growth and Enhances the Therapeutic Efficacy of Docetaxel via Akt Signaling.

Ge Jianchao J Wang Pengyu P Ma Hangbin H Zhang Jun J

Journal of oncology 20220310

Prostate cancer (PCa) has become a leading cause of cancer-associated incidence and mortality in men worldwide. However, most primary PCas relapse to castration-resistant PCa (CRPC) after androgen deprivation treatment. The current treatment for CRPC is based on chemotherapeutic drugs such as docetaxel, while the development of chemoresistance and severe side effects limit the therapeutic benefit. Solamargine, a natural alkaloid isolated from a traditional Chinese herbal medicine known as <i>Sol ...[more]

PMID: 35310915

Similar Datasets

Project description:BackgroundOver-activation of phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) signaling pathway is one of important mechanisms to promote castration resistant prostate cancer, the final stage of prostate cancer (PCa). Dysregulation of PP1-meditaed AKT dephosphorylation might contribute to such an event but is not fully understood. As a newly identified tumor suppressor, MIIP exerts its role in various types of cancer but has not been investigated in PCa.ResultsWe first demonstrated that overexpression of migration and invasion inhibitory protein (MIIP) in human PCa cell lines suppresses their growth while knockdown of MIIP does the opposite in vitro. Although MIIP has no effect on the expression of AR and its target genes or the nuclear translocation of AR in AR-positive PCa cells, MIIP overexpression significantly inhibits activation of AKT-mTOR pathway in both AR- positive and negative PCa cells whereas knockdown of MIIP enhances AKT-mTOR signaling. Using Western blot, immunofluorescence co-localization and co-immunoprecipitation analysis, we found that MIIP interacts with PP1α via its C-terminal part but does not affect its protein level. Importantly, silence of PP1α reversed the inhibitory effect of MIIP on AKT phosphorylation and cell growth in PCa cell lines, while MIIP∆C, which is incapable of interacting with PP1α, loses MIIP's effect, suggesting that MIIP exerts its roles via interaction with PP1α. Further, MIIP overexpression inhibits the growth of both AR- positive and negative PCa xenograft in nude mice. Finally, immunohistochemical staining of PCa tissue microarray showed that MIIP expression level is downregulated in PCa and negatively correlated with Gleason score of PCa.ConclusionWe discovered that MIIP is a novel suppressor of oncogenic AKT-mTOR signaling in PCa by facilitating PP1-meditaed AKT dephosphorylation. Our study further emphasized the tumor suppressive role of MIIP and illustrated a novel mechanism.

Project description:Glioblastoma is a high-grade glioma with poor prognosis even after surgery and standard therapy. Here, we asked whether carnosine (β-alanyl-L-histidine), a naturally occurring dipeptide, exert its anti-neoplastic effect on glioblastoma cells via PI3K/Akt/mTOR signaling. Therefore, glioblastoma cells from the lines U87 and T98G were exposed to carnosine, to the mTOR inhibitor rapamycin and to the PI3K inhibitor Ly-294,002. Pyruvate dehydrogenase kinase (PDK4) expression, known to be a target of PI3K/Akt/mTOR, and which is also affected by carnosine, was analyzed by RT-qPCR, and reporter gene assays with the human PDK4 promoter were performed. Cell viability was assessed by cell-based assays and mTOR and Akt phosphorylation by Western blotting. Rapamycin and Ly-294,002 increased PDK4 mRNA expression in both cell lines but significance was only reached in U87. Carnosine significantly increased expression in both lines. A significant combinatorial effect of carnosine was only detected in U87 when the dipeptide was combined with Ly-294,002. Reporter gene assays revealed no specific effect of carnosine on the human PDK4 promoter, whereas both inhibitors increased reporter gene expression. Rapamycin reduced phosphorylation of mTOR, and Ly-294,002 that of Akt. A significant reduction of Akt phosphorylation was observed in the presence of carnosine in U87 but not in T98G, and carnosine had no effect on mTOR phosphorylation. Cell viability as determined by ATP in cell lysates was reduced only in the presence of carnosine. We conclude that carnosine's anti-neoplastic effect is independent from PI3K/Akt/mTOR signaling. As the dipeptide reduced viability in tumor cells that do not respond to PI3K or mTOR inhibitors, it appears to be worth to further investigate the mechanisms by which carnosine exerts its anti-tumor effect and to consider it for therapy, especially as it is a naturally occurring compound that has already been used for the treatment of other diseases without indication of side-effects.

Dataset Information

Solamargine Inhibits Prostate Cancer Cell Growth and Enhances the Therapeutic Efficacy of Docetaxel via Akt Signaling.

Publications

Solamargine Inhibits Prostate Cancer Cell Growth and Enhances the Therapeutic Efficacy of Docetaxel via Akt Signaling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets