Proline metabolism supports metastasis formation and could be inhibited to selectively target metastasizing cancer cells.
Proline metabolism supports metastasis formation and could be inhibited to selectively target metastasizing cancer cells.
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DOI：
10.1038/ncomms15267
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发表时间：
2017-05-11
影响因子：
16.6
通讯作者：
Fendt SM
中科院分区：
文献类型：
--
作者：
Elia I;Broekaert D;Christen S;Boon R;Radaelli E;Orth MF;Verfaillie C;Grünewald TGP;Fendt SM
转移是癌症患者死亡的主要原因。转移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性尚不清楚。我们使用2D与3D培养来诱导乳腺癌细胞的细胞表型的转变。我们发现，脯氨酸催化剂通过脯氨酸脱氢酶（proline dehydrogenase，ADDH）支持乳腺癌细胞在3D培养中的生长。随后，我们将脯氨酸催化剂与体内转移形成联系起来。特别是，我们发现，PRODH表达和脯氨酸catalysts增加转移相比，原发性乳腺癌的患者和小鼠。此外，抑制BTH足以削弱原位4T1和EMT 6.5小鼠模型中肺转移瘤的形成，而对健康组织和器官功能没有不利影响。综上所述，我们发现，p53是一个潜在的药物靶点，用于抑制转移形成。转移性癌细胞重塑其代谢以支持其恶性表型。在这里，作者表明，在乳腺癌细胞系中获得转移表型导致脯氨酸催化剂增加，并且抑制该途径减少了两种小鼠模型中的肺转移形成。
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. Metastasizing cancer cells rewire their metabolism to support their malignant phenotypes. Here, the authors show that the acquisition of a metastatic phenotype in breast cancer cell lines results in increased proline catabolism and that inhibition of this pathway decreases lung metastasis formation in two mouse models.