Abstract 2587: Silibinin targets stemness and aberrant metabolic signaling in prostate cancer cells.

Abstract

Abstract Prostate cancer (PCA) is the 2nd leading cause of cancer-related deaths and accounts for 29% of all the cancers diagnosed in men in the United States. Although several curative measures including anti-androgen therapy, radiotherapy and chemotherapy exist for PCA management, significant morbidity is associated with them and a large number of men still succumb to this deadly malignancy every year. One of the obstacles in effectively targeting PCA cells is the limitation of current therapies to eliminate cancer stem cell (CSC) population, which is mainly responsible for the uncontrolled primary tumor growth, chemoresistance, disease relapse and metastasis. Therefore, additional measures are needed to target CSC in PCA. Silibinin is a bioactive flavonolignan that has been shown to exhibit potent anticancer effect against several cancers. We have previously reported that silibinin could inhibit PCA growth and progression via targeting cell cycle, epithelial-to-mesenchymal transition and angiogenesis. Here, for the first time we analyzed the efficacy of silibinin against prostate CSCs (PCSCs). Results showed that silibinin (50-200 μM) strongly inhibited the prostaspheres formation (‘a measure of stemness’) in human PCA PC3 and LNCaP cells. The strong inhibitory effect of silibinin was also observed against 2nd and 3rd generation prostaspheres of both the cell lines. Prostasphere differentiation in the presence of serum generated bulk of attached proliferating PCA cells which was strongly inhibited by silibinin treatment. Even when silibinin treatment was withdrawn, silibinin-treated prostaspheres largely lost their capability to form proliferating mass of attached cells. These results showed that silibinin inhibits key characteristics of self-renewal and differentiation of PCSCs. Since stemness and aberrant metabolism are hard-wired in cancer cells and fuel each other, next we studied the effect of silibinin on metabolic signaling in PCA cells. PC3 prostaspheres analyses by Western blotting revealed that silibinin (100-200 μM) treatment inhibited the expression of glucose transporter GLUT4. Further, silibinin also decreased the expression of hexokinase II and p-mTOR in prostaspheres. Similarly, silibinin treatment for 48 h in PC3 cells decreased the expression of hexokinase II, and pyruvate kinase M2, while increased the expression of lactate dehydrogenase 1, pyruvate dehydrogenase and phosphorylated acetyl CoA carboxylase. Together, these results suggest that silibinin targets the aerobic glycolysis (‘Warburg effect’) while it promotes Kreb cycle and oxidative phosphorylation in PCA cells. Also, silibinin enforced metabolic normalization restricts the availability of cellular building blocks, thereby induces cell division arrest in PCA cells. Overall, these results suggest that silibinin could be useful against PCA through targeting stemness and aberrant cancer cell metabolism. Citation Format: Gagan Deep, Anand Ramteke, Amandla Atilano-Roque, Chapla Agarwal, Rajesh Agarwal. Silibinin targets stemness and aberrant metabolic signaling in prostate cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2587. doi:10.1158/1538-7445.AM2013-2587