Canine Mammary Tumours (CMTs) exploit mitochondrial cholesterol for aggressive reprogramming

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2024-10-30 DOI:10.1016/j.bbadis.2024.167546

Liana Hardy , Brindha Kannan , Manuel Rigon , Genevieve Benton-Hawthorn , Renato L. Previdelli , Iris M. Reichler , Franco Guscetti , Mariusz P. Kowalewski , Michelangelo Campanella

{"title":"Canine Mammary Tumours (CMTs) exploit mitochondrial cholesterol for aggressive reprogramming","authors":"Liana Hardy , Brindha Kannan , Manuel Rigon , Genevieve Benton-Hawthorn , Renato L. Previdelli , Iris M. Reichler , Franco Guscetti , Mariusz P. Kowalewski , Michelangelo Campanella","doi":"10.1016/j.bbadis.2024.167546","DOIUrl":null,"url":null,"abstract":"<div><div>In human breast cancer the mitochondrial translocator protein (TSPO) aids pro-survival cellular response by facilitating the formation of mitochondrial contact sites with the nucleus termed Nucleus Associated Mitochondria (NAM). Here, we show that TSPO positively associates with the aggressiveness of tissues and cells isolated from Canine Mammary Tumours (CMTs).</div><div>TSPO is also readily upregulated in reprogrammed mammary tumour cells following long-term deprivation of oestrogen or exposure to the endocrine chemotherapeutic (ET) agent Tamoxifen. The latter triggers mitochondrial handling of cholesterol which is facilitated by TSPO whose upregulation reduces susceptibility to Tamoxifen. TSPO binding ligands boost, on the other hand, the efficacy of Tamoxifen and Chemotherapy agents. In aggressive canine mammary tumour cells, TSPO repression impairs the NF-kB pattern thus confirming the pro-survival role of the NAM uncovered in the human counterpart.</div><div>Mitochondrial cholesterol handling via TSPO emerges therefore as a signature in the aggressive reprogramming of CMTs thus advancing our understanding of the molecular mechanisms underpinning this pathology. A novel target mechanism to improve bio-marking and therapeutic protocols is here proposed.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 2","pages":"Article 167546"},"PeriodicalIF":4.2000,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochimica et biophysica acta. Molecular basis of disease","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0925443924005404","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

In human breast cancer the mitochondrial translocator protein (TSPO) aids pro-survival cellular response by facilitating the formation of mitochondrial contact sites with the nucleus termed Nucleus Associated Mitochondria (NAM). Here, we show that TSPO positively associates with the aggressiveness of tissues and cells isolated from Canine Mammary Tumours (CMTs).

TSPO is also readily upregulated in reprogrammed mammary tumour cells following long-term deprivation of oestrogen or exposure to the endocrine chemotherapeutic (ET) agent Tamoxifen. The latter triggers mitochondrial handling of cholesterol which is facilitated by TSPO whose upregulation reduces susceptibility to Tamoxifen. TSPO binding ligands boost, on the other hand, the efficacy of Tamoxifen and Chemotherapy agents. In aggressive canine mammary tumour cells, TSPO repression impairs the NF-kB pattern thus confirming the pro-survival role of the NAM uncovered in the human counterpart.

Mitochondrial cholesterol handling via TSPO emerges therefore as a signature in the aggressive reprogramming of CMTs thus advancing our understanding of the molecular mechanisms underpinning this pathology. A novel target mechanism to improve bio-marking and therapeutic protocols is here proposed.

查看原文本刊更多论文

犬乳腺肿瘤（CMT）利用线粒体胆固醇进行侵略性重编程。

在人类乳腺癌中，线粒体转运蛋白（TSPO）通过促进线粒体与细胞核（称为 "核相关线粒体"）接触点的形成，帮助细胞做出有利于生存的反应。在这里，我们发现 TSPO 与从犬乳腺肿瘤（CMT）中分离出来的组织和细胞的侵袭性呈正相关。在长期缺乏雌激素或暴露于内分泌化疗（ET）药物他莫昔芬后，TSPO 也很容易在重编程乳腺肿瘤细胞中上调。后者会触发线粒体对胆固醇的处理，而 TSPO 会促进线粒体对胆固醇的处理，其上调会降低对他莫昔芬的敏感性。另一方面，TSPO 结合配体可提高他莫昔芬和化疗药物的疗效。在侵袭性犬乳腺肿瘤细胞中，TSPO抑制会损害NF-kB模式，从而证实了在人类中发现的NAM的促生存作用。因此，通过 TSPO 处理线粒体胆固醇成为 CMT 攻击性重编程的一个特征，从而促进了我们对这种病理学的分子机制的了解。本文提出了一种新的目标机制，以改进生物标记和治疗方案。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.