PEPT1 is a proton-coupled peptide transporter that is up-regulated in PDAC cell lines and PDXs, with little expression in the normal pancreas. However, the relevance of this up-regulation to cancer progression and the mechanism of up-regulation have not been investigated. Herein, we show that PEPT1 is not just up-regulated in a large panel of PDAC cell lines and PDXs but is also functional and transport-competent. PEPT2, another proton-coupled peptide transporter, is also overexpressed in PDAC cell lines and PDXs, but is not functional due to its intracellular localization. Using glibenclamide as a pharmacological inhibitor of PEPT1, we demonstrate in cell lines in vitro and mouse xenografts in vivo that inhibition of PEPT1 reduces the proliferation of the cancer cells. These findings are supported by genetic knockdown of PEPT1 with shRNA, wherein the absence of the transporter significantly attenuates the growth of cancer cells, both in vitro and in vivo, suggesting that PEPT1 is critical for the survival of cancer cells. We also establish that the tumor-derived lactic acid (Warburg effect) in the tumor microenvironment supports the transport function of PEPT1 in the maintenance of amino acid nutrition in cancer cells by inducing MMPs and DPPIV to generate peptide substrates for PEPT1 and by generating a H+ gradient across the plasma membrane to energize PEPT1. Taken collectively, these studies demonstrate a functional link between PEPT1 and extracellular protein breakdown in the tumor microenvironment as a key determinant of pancreatic cancer growth, thus identifying PEPT1 as a potential therapeutic target for PDAC.

中文翻译：

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PEPT1对胰腺癌细胞的生长至关重要：一个可行的药物靶点

PEPT1 是一种质子偶联肽转运蛋白，在 PDAC 细胞系和 PDX 中上调，在正常胰腺中几乎没有表达。然而，尚未研究这种上调与癌症进展的相关性和上调机制。在此，我们表明 PEPT1 不仅在大量 PDAC 细胞系和 PDX 中上调，而且还具有功能和运输能力。PEPT2 是另一种质子偶联肽转运蛋白，也在 PDAC 细胞系和 PDX 中过度表达，但由于其细胞内定位而不起作用。使用格列本脲作为 PEPT1 的药理学抑制剂，我们在体外细胞系和体内小鼠异种移植物中证明了抑制 PEPT1 会减少癌细胞的增殖。这些发现得到了用 shRNA 基因敲除 PEPT1 的支持，其中转运蛋白的缺失显着减弱了体外和体内癌细胞的生长，表明 PEPT1 对癌细胞的存活至关重要。我们还确定，肿瘤微环境中的肿瘤来源乳酸（Warburg 效应）通过诱导 MMP 和 DPPIV 产生 PEPT1 的肽底物并产生 H+，支持 PEPT1 在维持癌细胞中氨基酸营养方面的转运功能。穿过质膜的梯度以激活 PEPT1。总的来说，这些研究证明了 PEPT1 与肿瘤微环境中细胞外蛋白分解之间的功能联系，这是胰腺癌生长的关键决定因素，从而将 PEPT1 确定为 PDAC 的潜在治疗靶点。