Abstract
Prostate cancer (PrCa) metastasis is the major cause of mortality and morbidity among men. Metastatic PrCa cells are typically adopted for aberrant glucose metabolism. Thus, chemophores that reprogram altered glucose metabolic machinery in cancer cells can be useful agent for the repression of PrCa metastasis. Herein, we report that cucurbitacin D (Cuc D) effectively inhibits glucose uptake and lactate production in metastatic PrCa cells via modulating glucose metabolism. This metabolic shift by Cuc D was correlated with decreased expression of GLUT1 by its direct binding as suggested by its proficient molecular docking (binding energy −8.5 kcal/mol). Cuc D treatment also altered the expression of key oncogenic proteins and miR-132 that are known to be involved in glucose metabolism. Cuc D (0.1 to 1 µM) treatment inhibited tumorigenic and metastatic potential of human PrCa cells via inducing apoptosis and cell cycle arrest in G2/M phase. Cuc D treatment also showed inhibition of tumor growth in PrCa xenograft mouse model with concomitant decrease in the expression of GLUT1, PCNA and restoration of miR-132. These results suggest that Cuc D is a novel modulator of glucose metabolism and could be a promising therapeutic modality for the attenuation of PrCa metastasis.
Highlights
Prostate cancer (PrCa) is one of the most common malignancies and second leading cause of cancer related deaths among American men [1]
Cancers 2019, 11, 364 that reprograming of cancer metabolism is a novel therapeutic strategy for PrCa management. These findings suggest that GLUT1 is a very important molecular target for PrCa therapy
Silencing the expression of miR-132 by using inhibitor concomitantly restored the expression of GLUT1 in cucurbitacin D (Cuc D) treated DU145 cells (Figure 4D). These results suggest that Cuc D treatment inhibits the expression of GLUT1 via restoration of miR-132 expression in PrCa cells
Summary
Prostate cancer (PrCa) is one of the most common malignancies and second leading cause of cancer related deaths among American men [1]. Emergence of castration resistant PrCa (CRPC) and chemo-resistance are some of the major hurdles in managing PrCa [2,3]. Accumulating evidence has shown that cancer cells are intricately sensitive to metabolic alterations that modify the metabolic homeostasis [4,5]. To maintain a fast growing need for intermediates, cancer cells reprogram their metabolic pathways. It has been reported that early and advanced stages of PrCa have quite different glucose metabolism [6], and this glycolytic metabolism displays a divergent profile in androgen-sensitive and insensitive PrCa cells [7]. A higher glucose uptake is required for rapid proliferation of androgen-insensitive PrCa cells [8]. Glucose transporters (GLUTs) are responsible for glucose uptake in cells by a mechanism of facilitated diffusion.
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