Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, 130021, Jilin Province, China.
Department of Orthopedics, The Second Hospital Jilin University, Changchun, 130021, Jilin Province, China.
Oncogene. 2024 Jan;43(2):136-150. doi: 10.1038/s41388-023-02878-1. Epub 2023 Nov 16.
Impaired macroautophagy/autophagy flux has been implicated in the treatment of prostate cancer (PCa). However, the mechanism underlying autophagy dysregulation in PCa remains unknown. In the current study, we investigated the role of diacylglycerol acyltransferases 1 (DGAT1) and its potential effects on cellular energy homeostasis and autophagy flux in PCa. The results of immunohistochemical staining suggested that DGAT1 expression was positively corrected with tumor stage and node metastasis, indicating DGAT1 is an important factor involved in the development and progression of PCa. Furthermore, targeting DGAT1 remarkably inhibited cell proliferation in vitro and suppressed PCa growth in xenograft models by triggering severe oxidative stress and subsequently autophagy flux blockage. Mechanically, DGAT1 promoted PCa progression by maintaining cellular energy homeostasis, preserving mitochondrial function, protecting against reactive oxygen species, and subsequently promoting autophagy flux via regulating lipid droplet formation. Moreover, we found that fenofibrate exhibits as an upstream regulator of DGAT1. Fenofibrate performed its anti-PCa effect involved the aforementioned mechanisms, and partially dependent on the regulation of DGAT1. Collectively. These findings indicate that DGAT1 regulates PCa lipid droplets formation and is essential for PCa progression. Targeting DGAT1 might be a promising method to control the development and progression of PCa. Schematic representation of DGAT1 affects autophagy flux by regulating lipid homeostasis and maintaining mitochondrial function in prostate cancer (PCa). PCa is characterized up-regulation of DGAT1, leading to the translocation of free fatty acids into lipid droplets, thereby preventing PCa cell from lipotoxicity. Inhibition of DGAT1 suppresses growth of PCa by inducing oxidative stress and subsequently autophagy flux blockage. Further, the current results revealed that fenofibrate exhibits as an upstream regulator of DGAT1, and fenofibrate plays an anti-PCa role partially dependent on the regulation of DGAT1, suggesting a potential therapeutic approach to ameliorate this refractory tumor.
自噬通量的受损与前列腺癌（PCa）的治疗有关。然而，PCa 中自噬失调的机制尚不清楚。在本研究中，我们研究了二酰基甘油酰基转移酶 1（DGAT1）的作用及其对 PCa 细胞能量稳态和自噬通量的潜在影响。免疫组织化学染色的结果表明，DGAT1 的表达与肿瘤分期和淋巴结转移呈正相关，表明 DGAT1 是参与 PCa 发生和发展的重要因素。此外，靶向 DGAT1 通过触发严重的氧化应激，随后阻断自噬通量，显著抑制体外细胞增殖，并在异种移植模型中抑制 PCa 生长。在机制上，DGAT1 通过维持细胞能量稳态、保护线粒体功能、防止活性氧产生，从而促进自噬通量，从而促进 PCa 的进展。此外，我们发现非诺贝特是 DGAT1 的上游调节物。非诺贝特通过上述机制发挥其抗 PCa 作用，部分依赖于 DGAT1 的调节。总之，这些发现表明 DGAT1 调节 PCa 脂滴的形成，是 PCa 进展所必需的。靶向 DGAT1 可能是控制 PCa 发展和进展的一种有前途的方法。图中示意 DGAT1 通过调节脂质稳态和维持线粒体功能影响前列腺癌（PCa）中的自噬通量。PCa 中 DGAT1 上调，导致游离脂肪酸易位到脂滴中，从而防止 PCa 细胞发生脂毒性。DGAT1 的抑制通过诱导氧化应激和随后的自噬通量阻断来抑制 PCa 的生长。此外，目前的结果表明，非诺贝特是 DGAT1 的上游调节物，非诺贝特发挥抗 PCa 作用部分依赖于 DGAT1 的调节，这表明改善这种难治性肿瘤的潜在治疗方法。
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