Background: Cancer cells exhibit altered metabolism whereby glucose is preferentially utilized to produce lactate through aerobic glycolysis. The increase in lactate production creates an acidic microenvironment that supports tumor progression and metastasis. Human small leucine zipper protein (sLZIP) is involved in the transcriptional regulation of genes related to migration and invasion of prostate cancer. However, the role of sLZIP in modulating glucose metabolism in prostate cancer remains unknown. This study investigates whether sLZIP regulates the transcription of glycolysis-related genes to promote metabolic reprogramming in prostate cancer. Methods: Depletion of sLZIP resulted in the downregulation of several glycolytic genes, including glucose transporter 1, phosphofructokinase liver type, phosphoglycerate kinase 1 (PGK1), and lactate dehydrogenase. Among these, only PGK1 showed a prominent dose-dependent decrease in mRNA and protein expression after sLZIP silencing. Results: Mechanistically, increasing or decreasing sLZIP affected the promoter activity of PGK1 in a similar manner. Moreover, the absence of sLZIP attenuated the maximum glycolytic rate in prostate cancer cells. These results were further supported by a reduction in lactate secretion, glucose uptake, and ATP production in sLZIP-knockout prostate cancer cells. sLZIP deficiency hindered cancer growth, as demonstrated by proliferation assays. However, overexpression of PGK1 in sLZIP knockout cells resulted in recovery of aerobic glycolysis. Results of the xenograft experiment revealed that mice injected with sLZIP knockout cells exhibited a decrease in tumor mass compared to those injected with control cells. Conclusion: These findings suggest that sLZIP contributes to the metabolic reprogramming of prostate cancer cells via the transcriptional regulation of PGK1.
背景：癌细胞表现出代谢改变，倾向于通过有氧糖酵解将葡萄糖转化为乳酸。乳酸产量增加形成酸性微环境，促进肿瘤进展和转移。人类小亮氨酸拉链蛋白（sLZIP）参与前列腺癌迁移侵袭相关基因的转录调控，但其在前列腺癌葡萄糖代谢调节中的作用尚不明确。本研究旨在探讨sLZIP是否通过调控糖酵解相关基因转录促进前列腺癌代谢重编程。 方法：敲除sLZIP导致多个糖酵解基因表达下调，包括葡萄糖转运蛋白1、磷酸果糖激酶肝型、磷酸甘油酸激酶1（PGK1）及乳酸脱氢酶。其中仅PGK1在sLZIP沉默后呈现显著的剂量依赖性mRNA和蛋白表达下降。 结果：机制研究表明，sLZIP表达水平变化以相似方式影响PGK1启动子活性。sLZIP缺失会降低前列腺癌细胞的最大糖酵解速率，该结果在sLZIP敲除细胞中通过乳酸分泌减少、葡萄糖摄取下降和ATP生成降低得到进一步验证。增殖实验显示sLZIP缺陷会抑制肿瘤生长，但在sLZIP敲除细胞中过表达PGK1可恢复有氧糖酵解功能。异种移植实验表明，注射sLZIP敲除细胞的小鼠肿瘤质量较对照组显著降低。 结论：本研究提示sLZIP通过转录调控PGK1促进前列腺癌细胞代谢重编程。
肿瘤(癌症)患者之家