Silencing of matrix metalloprotease-12 delays the progression of castration-resistant prostate cancer by regulating autophagy and lipolysis.

IF 1.9 4区 医学 Q2 BIOLOGY Brazilian Journal of Medical and Biological Research Pub Date : 2024-03-18 eCollection Date: 2024-01-01 DOI:10.1590/1414-431X2024e13351
Xiaoyu Zheng, Xiaoqin Xie, Wei Wang, Liang Wang, Bing Tan
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Abstract

The complex pathogenesis of castration-resistant prostate cancer (CRPC) makes it challenging to identify effective treatment methods. Matrix metalloproteinase (MMP)-12 can degrade elastin as well as various extracellular matrix (ECM) components, which is associated with cancer progression. However, the relationship between MMP-12 and CRPC progression is poorly understood. In this study, we observed the effect of MMP-12 on the progression of CRPC and further explored its potential mechanism of action. High levels of MMP-12 were observed in patients with CRPC. We therefore developed cell co-culture and mouse models to study the function of MMP-12. Silencing MMP-12 in CRPC cells disrupted lipid utilization and autophagy marker expression via the CD36/CPT1 and P62/LC3 pathways, respectively, leading to reduced CRPC cell migration and invasion. Moreover, animal experiments confirmed that MMP-12-knockdown CRPC xenograft tumors exhibited reduced tumor growth, and the mechanisms involved the promotion of cancer cell autophagy and the inhibition of lipid catabolism. According to our results, MMP-12 played important roles in the progression of CRPC by disrupting adipocyte maturation and regulating cancer migration and invasion via the modulation of autophagy and lipid catabolism pathways.

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沉默基质金属蛋白酶-12可通过调节自噬和脂肪分解延缓耐受性前列腺癌的进展。
去势抵抗性前列腺癌(CRPC)的发病机制十分复杂,因此确定有效的治疗方法具有挑战性。基质金属蛋白酶(MMP)-12可降解弹性蛋白以及各种细胞外基质(ECM)成分,这与癌症进展有关。然而,人们对 MMP-12 与 CRPC 进展之间的关系知之甚少。在本研究中,我们观察了 MMP-12 对 CRPC 进展的影响,并进一步探讨了其潜在的作用机制。在CRPC患者体内观察到了高水平的MMP-12。因此,我们开发了细胞共培养和小鼠模型来研究MMP-12的功能。通过CD36/CPT1和P62/LC3途径沉默CRPC细胞中的MMP-12,可分别破坏脂质利用和自噬标记物的表达,从而减少CRPC细胞的迁移和侵袭。此外,动物实验证实,MMP-12敲除的CRPC异种移植瘤表现出肿瘤生长减慢,其机制涉及促进癌细胞自噬和抑制脂质分解。我们的研究结果表明,MMP-12通过调节自噬和脂质代谢途径,破坏脂肪细胞的成熟并调控癌症的迁移和侵袭,从而在CRPC的进展过程中发挥重要作用。
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来源期刊
CiteScore
4.00
自引率
0.00%
发文量
129
审稿时长
2 months
期刊介绍: The Brazilian Journal of Medical and Biological Research, founded by Michel Jamra, is edited and published monthly by the Associação Brasileira de Divulgação Científica (ABDC), a federation of Brazilian scientific societies: - Sociedade Brasileira de Biofísica (SBBf) - Sociedade Brasileira de Farmacologia e Terapêutica Experimental (SBFTE) - Sociedade Brasileira de Fisiologia (SBFis) - Sociedade Brasileira de Imunologia (SBI) - Sociedade Brasileira de Investigação Clínica (SBIC) - Sociedade Brasileira de Neurociências e Comportamento (SBNeC).
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