Inhibition of GLS suppresses proliferation and promotes apoptosis in prostate cancer

Junfeng Zhang,Shiyu Mao,Yadong Guo,Yong Huang,Xudong Yao,Yuan Wu

doi:10.1042/bsr20181826

Junfeng Zhang, Shiyu Mao + Show 4 more

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https://doi.org/10.1042/bsr20181826

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Abstract

Altered glutamine metabolism is a hallmark of cancer growth, forming the theoretical basis for development of metabolic therapies as cancer treatments. Glutaminase (GLS), a crucial enzyme involved in the regulation of glutamine metabolism, has been reported to play crucial roles in cancer development. However, the precise function of GLS in prostate cancer (PCa) remains unclear. The purpose of the present study was to assess the GLS expression and its clinical significance in PCa. We found that GLS was significantly up-regulated in PCa tissues and cell lines. High expression of GLS was significantly associated with Gleason score (P=0.001) and Tumor stage (P=0.015). Functionally, we silenced GLS in PCa cell lines and revealed that GLS knockdown largely blunted the proliferation of DU145 and PC-3 cells. Mechanistically, we demonstrated that knockdown of GLS induced apoptosis and cell cycle arrest. Moreover, we observed that the expressions of Bax were increased while the levels of cyclinD1 and Bcl-2 were decreased after knockdown of GLS in PCa cells. Importantly, through Western blot analysis, we identified that GLS knockdown dramatically suppressed Wnt/β-catenin pathway. Taken together, GLS is a novel oncogene in PCa and may be a potential treatment target for PCa patients.

Highlights

Prostate cancer (PCa) is one of the most common malignancy among men and is the second major cause of male cancer-related deaths in the United States [1]
We found that GLS is overexpressed in PCa tissues and cell lines compared with the adjacent normal tissues and the normal prostate epithelial cell line RWPE-1
Results of quantitative real-time PCR (qRT-PCR) indicated that GLS is significantly overexpressed in PCa tissues compared with normal prostate tissues (Figure 1A)

Summary

Introduction

Prostate cancer (PCa) is one of the most common malignancy among men and is the second major cause of male cancer-related deaths in the United States [1]. In 2016, the American Cancer Society reported that approximately 180890 new PCa cases and 26120 deaths occurred in United States [2]. Most PCa cases are treatable among men diagnosed with localized or regional disease as evidenced by a 100% 5-year survival rate. The 5-year survival rate drops to 29% for patients who develop metastatic disease [3]. Glutaminase (GLS), which converts glutamine into glutamate, plays a vital role in up-regulating cell metabolism for tumor cell growth [4]. Many oncogenes and tumor suppressors have been linked to the regulation of GLS expression and glutamine metabolism [12]. Its precise mechanism involved in the carcinogenesis of PCa is yet to be elucidated

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