Department of Pathology, Duke University School of Medicine, Durham, NC 27710.
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710.
Proc Natl Acad Sci U S A. 2021 Mar 30;118(13). doi: 10.1073/pnas.2012748118.
Cellular metabolism in cancer is significantly altered to support the uncontrolled tumor growth. How metabolic alterations contribute to hormonal therapy resistance and disease progression in prostate cancer (PCa) remains poorly understood. Here we report a glutaminase isoform switch mechanism that mediates the initial therapeutic effect but eventual failure of hormonal therapy of PCa. Androgen deprivation therapy inhibits the expression of kidney-type glutaminase (KGA), a splicing isoform of glutaminase 1 (GLS1) up-regulated by androgen receptor (AR), to achieve therapeutic effect by suppressing glutaminolysis. Eventually the tumor cells switch to the expression of glutaminase C (GAC), an androgen-independent GLS1 isoform with more potent enzymatic activity, under the androgen-deprived condition. This switch leads to increased glutamine utilization, hyperproliferation, and aggressive behavior of tumor cells. Pharmacological inhibition or RNA interference of GAC shows better treatment effect for castration-resistant PCa than for hormone-sensitive PCa in vitro and in vivo. In summary, we have identified a metabolic function of AR action in PCa and discovered that the GLS1 isoform switch is one of the key mechanisms in therapeutic resistance and disease progression.
肿瘤细胞的代谢会发生显著改变，以支持肿瘤的失控生长。代谢改变如何导致前列腺癌（PCa）对激素治疗的耐药性和疾病进展仍然知之甚少。在这里，我们报告了一种谷氨酰胺酶同工型转换机制，该机制介导了 PCa 激素治疗的初始治疗效果，但最终失败。去势治疗通过抑制谷氨酰胺分解来抑制肾型谷氨酰胺酶（KGA）的表达，KGA 是雄激素受体（AR）上调的谷氨酰胺酶 1（GLS1）的剪接同工型，从而达到治疗效果。最终，在去雄激素条件下，肿瘤细胞切换为表达谷氨酰胺酶 C（GAC），一种具有更强酶活性的雄激素非依赖性 GLS1 同工型。这种转换导致肿瘤细胞的谷氨酰胺利用率增加、过度增殖和侵袭行为增加。体外和体内实验表明，GAC 的药理学抑制或 RNA 干扰对去势抵抗性 PCa 的治疗效果优于对激素敏感性 PCa。总之，我们已经确定了 AR 作用在 PCa 中的代谢功能，并发现 GLS1 同工型转换是治疗耐药性和疾病进展的关键机制之一。
