7-脱氢胆固醇在头颈部鳞状细胞癌内质网应激及凋亡中的作用。

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-05-31 DOI:10.1016/j.canlet.2025.217842

Bok-Soon Lee , Yea-In Park , Hengtian Liu , Sang Gyu Kim , Hyo Jeong Kim , Ji-Hye Choi , Si Hyun Rho , Joselyn Padilla , Jin Roh , Hyun Goo Woo , Hae Jin Seo , Man Ho Choi , Yu-Jin Jeong , Evan C. Lien , Syed Hassan Mehdi , Dongjoon Lee , Donghoon Yoon , Chul-Ho Kim , Jiyoung Lee

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引用次数: 0

摘要

维持癌细胞存活的代谢途径的改变通常提供了有希望的治疗途径。本研究表明，增强的新生胆固醇生物合成对头颈部鳞状细胞癌（HNSCC）的存活至关重要。与正常组织相比，HNSCC组织的转录组学分析发现了类固醇和胆固醇代谢的严重失调。抑制介导胆固醇生物合成的两种关键酶DHCR7和DHCR24，即使在胆固醇水平恢复后，也会诱导HNSCC细胞凋亡。代谢组学分析显示，7-脱氢胆固醇（7-DHC）在DHCR7或DHCR24抑制下积累，引发内质网（ER）应激并进一步促进细胞死亡。这些发现表明，HNSCC细胞通过提高DHCR7和DHCR24水平调节7-DHC水平来适应内质网应激，突出了HNSCC的代谢脆弱性，并证明了胆固醇代谢与内质网应激在癌细胞活力中的直接联系。

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The role of 7-dehydrocholesterol in inducing ER stress and apoptosis of head and neck squamous cell carcinoma

Alterations of metabolic pathways that sustain cancer cell survival often offer promising therapeutic avenues. Here, we show that enhanced de novo cholesterol biosynthesis is crucial for the survival of head and neck squamous cell carcinoma (HNSCC). Transcriptomic analysis of HNSCC tissues identified profound dysregulation in steroid and cholesterol metabolism compared to normal tissues. Inhibition of two key enzymes, DHCR7 and DHCR24, which mediate cholesterol biosynthesis, induced apoptosis in HNSCC cells, even when cholesterol levels were restored. Metabolomic profiling revealed the accumulation of 7-dehydrocholesterol (7-DHC) upon DHCR7 or DHCR24 inhibition, triggering endoplasmic reticulum (ER) stress and promoting further cell death. These findings suggest that HNSCC cells adapt to ER stress by modulating 7-DHC levels through enhancing DHCR7 and DHCR24 levels, highlighting a metabolic vulnerability in HNSCC and demonstrating a direct link between cholesterol metabolism and ER stress in cancer cell viability.

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来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.