Prolyl Carboxypeptidase Maintains Receptor Tyrosine Kinase Signaling and Is a Potential Therapeutic Target in Triple Negative Breast Cancer.
Prolyl Carboxypeptidase Maintains Receptor Tyrosine Kinase Signaling and Is a Potential Therapeutic Target in Triple Negative Breast Cancer.
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DOI：
10.3390/cancers14030739
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发表时间：
2022-01-31
期刊：
影响因子：
5.2
通讯作者：
Maki CG
中科院分区：
文献类型：
--
作者：
Duan L;Calhoun S;Perez RE;Macias V;Mir F;Pergande MR;Gattuso P;Borgia JA;Maki CG
三阴性乳腺癌（TNBC）是一种侵袭性癌症，治疗选择有限，预后差。我们的研究表明，一种名为脯氨酸羧基肽酶（PRCP）的蛋白质是TNBC的潜在治疗靶点。我们发现肿瘤中高水平的PRCP与TNBC患者预后较差相吻合。用小分子抑制剂抑制PRCP可阻断TNBC细胞和肿瘤生长，并抑制几种受体酪氨酸激酶（rtk）的活性，rtk是位于细胞表面的蛋白质，对癌症的发生和进展很重要。我们的研究结果表明，PRCP是TNBC的一个新的预后因素，可以开发特异性的PRCP抑制剂来治疗TNBC。TNBC是一种侵袭性癌症亚型，治疗选择有限，预后差。需要新的治疗靶点来改善TNBC患者的预后。PRCP是一种溶酶体丝氨酸蛋白酶，当倒数第二种氨基酸是脯氨酸时，它可以切割肽底物。PRCP在TNBC或其他癌症中的作用及其作为治疗靶点的潜力尚未得到测试。在目前的研究中，我们发现PRCP的高肿瘤表达与TNBC患者预后较差和早期复发相关。敲除PRCP或用小分子PRCP抑制剂治疗可阻断TNBC细胞系的增殖和存活，并抑制小鼠TNBC肿瘤的生长。在机制上，我们发现PRCP维持来自多受体酪氨酸激酶（rtk）的信号传导，可能是通过促进rtk和g蛋白偶联受体（gpcr）之间的串扰。最后，我们发现当PRCP抑制剂与EGFR和ErbB2抑制剂拉帕替尼联合使用时，可以协同杀死TNBC细胞。我们的研究结果表明，PRCP是TNBC患者预后的潜在预后标志物，也是TNBC治疗的新靶点。
Triple negative breast cancer (TNBC) is an aggressive cancer type with limited treatment options and poor prognosis. Our research has revealed that a protein called prolylcarboxypeptidase (PRCP) is a potential therapy target for TNBC. We found that high levels of PRCP in tumors coincides with worse prognosis in TNBC patients. Inhibition of PRCP with a small molecule inhibitor blocked TNBC cell and tumor growth and inhibited the activity of several receptor tyrosine kinases (RTKs), proteins that are located on the surface of cells and that are important for cancer development and progression. Our findings suggest that PRCP is a novel prognostic factor for TNBC and that specific inhibitors of PRCP could be developed for TNBC treatment. TNBC is an aggressive cancer sub-type with limited treatment options and poor prognosis. New therapeutic targets are needed to improve outcomes in TNBC patients. PRCP is a lysosomal serine protease that cleaves peptide substrates when the penultimate amino acid is proline. A role for PRCP in TNBC or other cancers, and its potential as a therapy target has not yet been tested. In the current study, we found high tumor expression of PRCP associates with worse outcome and earlier recurrence in TNBC patients. Knockdown of PRCP or treatment with a small molecule PRCP inhibitor blocked proliferation and survival in TNBC cell lines and inhibited growth of TNBC tumors in mice. Mechanistically, we found PRCP maintains signaling from multiple receptor tyrosine kinases (RTKs), potentially by promoting crosstalk between RTKs and G-protein coupled receptors (GPCRs). Lastly, we found that the PRCP inhibitor caused synergistic killing of TNBC cells when combined with the EGFR and ErbB2 inhibitor lapatinib. Our results suggest that PRCP is potential prognostic marker for TNBC patient outcome and a novel therapeutic target for TNBC treatment.
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