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脯氨酸代谢支持转移形成，并且可以被抑制以选择性地针对转移的癌细胞。

Proline metabolism supports metastasis formation and could be inhibited to selectively target metastasizing cancer cells.

机构信息

Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, VIB, Herestraat 49, Leuven 3000, Belgium.

Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, Leuven 3000, Belgium.

出版信息

Nat Commun. 2017 May 11;8:15267. doi: 10.1038/ncomms15267.

DOI:10.1038/ncomms15267
PMID:28492237
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5437289/
Abstract

Metastases are the leading cause of mortality in patients with cancer. Metastasis formation requires cancer cells to adapt their cellular phenotype. However, how metabolism supports this adaptation of cancer cells is poorly defined. We use 2D versus 3D cultivation to induce a shift in the cellular phenotype of breast cancer cells. We discover that proline catabolism via proline dehydrogenase (Prodh) supports growth of breast cancer cells in 3D culture. Subsequently, we link proline catabolism to in vivo metastasis formation. In particular, we find that PRODH expression and proline catabolism is increased in metastases compared to primary breast cancers of patients and mice. Moreover, inhibiting Prodh is sufficient to impair formation of lung metastases in the orthotopic 4T1 and EMT6.5 mouse models, without adverse effects on healthy tissue and organ function. In conclusion, we discover that Prodh is a potential drug target for inhibiting metastasis formation.

摘要

转移是癌症患者死亡的主要原因。转移的形成需要癌细胞适应其细胞表型。然而，代谢如何支持癌细胞的这种适应还没有明确的定义。我们使用 2D 与 3D 培养来诱导乳腺癌细胞的细胞表型发生转变。我们发现脯氨酸脱氢酶（Prodh）通过分解脯氨酸来支持乳腺癌细胞在 3D 培养中的生长。随后，我们将脯氨酸代谢与体内转移形成联系起来。具体来说，我们发现与患者和小鼠的原发性乳腺癌相比，转移中 PRODH 的表达和脯氨酸代谢增加。此外，抑制 Prodh 足以损害 4T1 和 EMT6.5 小鼠模型中的肺转移形成，而对健康组织和器官功能没有不良影响。总之，我们发现 Prodh 是抑制转移形成的潜在药物靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74c9/5437289/12058c872df7/ncomms15267-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74c9/5437289/3fa3fb1662a6/ncomms15267-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74c9/5437289/a5716e8caf35/ncomms15267-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74c9/5437289/949bba5d3cee/ncomms15267-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74c9/5437289/b22247eed65e/ncomms15267-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74c9/5437289/b9b2ba9b2112/ncomms15267-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74c9/5437289/8928e2071196/ncomms15267-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74c9/5437289/12058c872df7/ncomms15267-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74c9/5437289/3fa3fb1662a6/ncomms15267-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74c9/5437289/a5716e8caf35/ncomms15267-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74c9/5437289/949bba5d3cee/ncomms15267-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74c9/5437289/b22247eed65e/ncomms15267-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74c9/5437289/b9b2ba9b2112/ncomms15267-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74c9/5437289/8928e2071196/ncomms15267-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74c9/5437289/12058c872df7/ncomms15267-f7.jpg

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[6]
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[8]
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[10]
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本文引用的文献

[1]
Early dissemination seeds metastasis in breast cancer.

Nature. 2016-12-22

[2]
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Metab Eng. 2016-11-12

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Breast Cancer-Derived Lung Metastases Show Increased Pyruvate Carboxylase-Dependent Anaplerosis.

Cell Rep. 2016-10-11

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Cell Metab. 2016-9-8

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Proline biosynthesis augments tumor cell growth and aerobic glycolysis: involvement of pyridine nucleotides.

Sci Rep. 2015-11-24

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