CYP19A1 regulates chemoresistance in colorectal cancer through modulation of estrogen biosynthesis and mitochondrial function.

IF 6 3区 医学 Q1 CELL BIOLOGY
Yang Wang, Qiang Ji, Ning Cao, Guijie Ge, Xiaomin Li, Xiangdong Liu, Yanqi Mi
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引用次数: 0

Abstract

Chemoresistance remains a major challenge in the effective treatment of colorectal cancer (CRC), contributing to poor patient outcomes. While the molecular mechanisms underlying chemoresistance are complex and multifaceted, emerging evidence suggests that altered mitochondrial function and hormone signaling play crucial roles. In this study, we investigated the role of CYP19A1, a key enzyme in estrogen biosynthesis, in regulating chemoresistance in CRC. Using a combination of in vitro functional assays, transcriptomic analysis, and clinical data mining, we demonstrate that CYP19A1 expression is significantly upregulated in CRC cells and patient-derived samples compared to normal controls. Mechanistically, we found that CYP19A1 regulates chemoresistance through modulation of mitochondrial function and complex I activity, which is mediated by CYP19A1-dependent estrogen biosynthesis. Notably, targeted inhibition of CYP19A1 and complex I using specific inhibitors effectively reversed the chemoresistance of CRC cells to chemotherapeutic drugs. Moreover, analysis of the TCGA CRC dataset revealed that high CYP19A1 expression correlates with poor overall survival in chemotherapy-treated patients. Taken together, our findings uncover a novel role for CYP19A1 in regulating chemoresistance in CRC through modulation of mitochondrial function and estrogen signaling, and highlight the potential of targeting the CYP19A1/estrogen/complex I axis as a therapeutic strategy to overcome chemoresistance and improve patient outcomes.

CYP19A1通过调节雌激素的生物合成和线粒体功能调节结直肠癌的化疗耐药性
化疗耐药性仍是有效治疗结直肠癌(CRC)的一大挑战,导致患者预后不佳。虽然化疗耐药性的分子机制复杂而多面,但新出现的证据表明线粒体功能和激素信号转导的改变起着至关重要的作用。在本研究中,我们研究了雌激素生物合成的关键酶 CYP19A1 在调节 CRC 化疗耐药性中的作用。通过体外功能测试、转录组分析和临床数据挖掘相结合的方法,我们证明与正常对照组相比,CYP19A1 在 CRC 细胞和患者来源样本中的表达显著上调。从机理上讲,我们发现 CYP19A1 通过调节线粒体功能和复合体 I 活性来调节化疗耐药性,而线粒体功能和复合体 I 活性是由 CYP19A1 依赖性雌激素生物合成介导的。值得注意的是,使用特异性抑制剂靶向抑制 CYP19A1 和复合体 I 能有效逆转 CRC 细胞对化疗药物的化疗耐药性。此外,对 TCGA CRC 数据集的分析表明,CYP19A1 的高表达与化疗患者的总生存率低有关。综上所述,我们的发现揭示了 CYP19A1 通过调节线粒体功能和雌激素信号转导在调节 CRC 化疗耐药性中的新作用,并强调了靶向 CYP19A1/雌激素/复合物 I 轴作为克服化疗耐药性和改善患者预后的治疗策略的潜力。
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来源期刊
自引率
1.70%
发文量
17
审稿时长
14 weeks
期刊介绍: Cancer & Metabolism welcomes studies on all aspects of the relationship between cancer and metabolism, including: -Molecular biology and genetics of cancer metabolism -Whole-body metabolism, including diabetes and obesity, in relation to cancer -Metabolomics in relation to cancer; -Metabolism-based imaging -Preclinical and clinical studies of metabolism-related cancer therapies.
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