Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
Cell Death Dis. 2023 Oct 16;14(10):682. doi: 10.1038/s41419-023-06200-5.
Cancer stem-like cells (CSCs) contribute to cancer metastasis, drug resistance and tumor relapse, yet how amino acid metabolism promotes CSC maintenance remains exclusive. Here, we identify that proline synthetase PYCR1 is critical for breast cancer stemness and tumor growth. Mechanistically, PYCR1-synthesized proline activates cGMP-PKG signaling to enhance cancer stem-like traits. Importantly, cGMP-PKG signaling mediates psychological stress-induced cancer stem-like phenotypes and tumorigenesis. Ablation of PYCR1 markedly reverses psychological stress-induced proline synthesis, cGMP-PKG signaling activation and cancer progression. Clinically, PYCR1 and cGMP-PKG signaling components are highly expressed in breast tumor specimens, conferring poor survival in breast cancer patients. Targeting proline metabolism or cGMP-PKG signaling pathway provides a potential therapeutic strategy for breast patients undergoing psychological stress. Collectively, our findings unveil that PYCR1-enhanced proline synthesis displays a critical role in maintaining breast cancer stemness.
癌症干细胞样细胞 (CSCs) 促进癌症转移、耐药性和肿瘤复发，但氨基酸代谢如何促进 CSC 的维持仍然是个谜。在这里，我们发现脯氨酸合成酶 PYCR1 对乳腺癌干细胞特性和肿瘤生长至关重要。在机制上，PYCR1 合成的脯氨酸激活 cGMP-PKG 信号通路，增强癌症干细胞样特征。重要的是，cGMP-PKG 信号通路介导心理应激诱导的癌症干细胞样表型和肿瘤发生。PYCR1 的缺失显著逆转了心理应激诱导的脯氨酸合成、cGMP-PKG 信号通路激活和癌症进展。临床上，PYCR1 和 cGMP-PKG 信号通路的组成部分在乳腺癌肿瘤标本中高度表达，这使得乳腺癌患者的生存预后较差。靶向脯氨酸代谢或 cGMP-PKG 信号通路为经历心理应激的乳腺癌患者提供了一种潜在的治疗策略。总的来说，我们的研究结果揭示了 PYCR1 增强的脯氨酸合成在维持乳腺癌干细胞特性方面发挥着关键作用。
