TRIB3 inhibition by palbociclib sensitizes prostate cancer to ferroptosis via downregulating SOX2/SLC7A11 expression.

IF 6.1 2区生物学 Q1 CELL BIOLOGY Cell Death Discovery Pub Date : 2024-10-03 DOI:10.1038/s41420-024-02152-7

Yangyi Zhang, Chenyu Liu, Yalan Yang, He Ren, Tianyi Ren, Yinuo Huang, Shinan Zhang, Qiang Sun, Hongyan Huang

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Abstract

Palbociclib is a CDK4/6 inhibitor approved for the treatment of breast cancer by suppressing cell proliferation. However, monotherapy with palbociclib was discouraging in prostate cancer, calling for a mechanism-based effective therapy. In this study, we reported in prostate cancer that palbociclib is a potent sensitizer of ferroptosis, which is worked out by downregulating the expression of TRIB3, a gene highly expressed in prostate cancer. Specifically, TRIB3 knockdown augmented the response of prostate cancer cells to ferroptosis inducers, whereas, TRIB3 overexpression rescued prostate cancer cells from palbociclib-induced ferroptosis. Mechanistically, TRIB3 inhibition by palbociclib resulted in downregulation of SOX2, which subsequently led to compromised expression of SLC7A11, a cystine/glutamate antiporter that counteracts ferroptosis. Functionally, a combined treatment of palbociclib with ferroptosis inducer significantly suppressed prostate cancer growth in a xenograft tumor model. Together, these results uncover an essential role of TRIB3/SOX2/SLC7A11 axis in palbociclib-induced ferroptosis, suggesting palbociclib a promising targeted therapy in combine with ferroptosis induction for the treatment of prostate cancer.

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帕博西尼（palbociclib）抑制TRIB3可通过下调SOX2/SLC7A11的表达，使前列腺癌对铁变态反应敏感。

Palbociclib 是一种 CDK4/6 抑制剂，通过抑制细胞增殖被批准用于治疗乳腺癌。然而，palbociclib单药治疗前列腺癌的效果并不理想，因此需要一种基于机制的有效疗法。在这项研究中，我们报道了帕博西尼在前列腺癌中是一种强效的促铁蛋白生成剂，它是通过下调前列腺癌高表达基因TRIB3的表达来实现的。具体来说，TRIB3基因敲除可增强前列腺癌细胞对铁变态反应诱导剂的反应，而TRIB3基因过表达则可挽救前列腺癌细胞免受帕博西尼诱导的铁变态反应的影响。从机理上讲，帕博西尼抑制TRIB3会导致SOX2下调，进而影响SLC7A11的表达，SLC7A11是一种胱氨酸/谷氨酸抗转运体，可对抗铁变态反应。在功能上，palbociclib 与铁突变诱导剂联合治疗可显著抑制异种移植肿瘤模型中前列腺癌的生长。这些结果揭示了TRIB3/SOX2/SLC7A11轴在帕博西尼诱导铁氧化过程中的重要作用，表明帕博西尼与铁氧化诱导剂联合治疗前列腺癌是一种很有前景的靶向疗法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.