Carboxypeptidase A4 (CPA4) is an exopeptidase that cleaves peptide bonds at the C-terminal domain within peptides and proteins. It preferentially cleaves peptides with terminal aromatic or branched chain amino acid residues such as phenylalanine, tryptophan, or leucine. CPA4 was first discovered in prostate cancer cells, but it is now known to be expressed in various tissues throughout the body. Its physiologic expression is governed by latexin, a noncompetitive endogenous inhibitor of CPA4. Nevertheless, the overexpression of CPA4 has been associated with the progression and aggressiveness of many malignancies, including prostate, pancreatic, breast and lung cancer, to name a few. CPA4’s role in cancer has been attributed to its disruption of many cellular signaling pathways, e.g., PI3K-AKT-mTOR, STAT3-ERK, AKT-cMyc, GPCR, and estrogen signaling. The dysregulation of these pathways by CPA4 could be responsible for inducing epithelial--mesenchymal transition (EMT), tumor invasion and drug resistance. Although CPA4 has been found to regulate cancer aggressiveness and poor prognosis, no comprehensive review summarizing the role of CPA4 in cancer is available so far. In this review, we provide a brief description of peptidases, their classification, history of CPA4, mechanism of action of CPA4 as a peptidase, its expression in various tissues, including cancers, its role in various tumor types, the associated molecular pathways and cellular processes. We further discuss the limitations of current literature linking CPA4 to cancers and challenges that prevent using CPA4 as a biomarker for cancer aggressiveness and predicting drug response and highlight a number of future strategies that can help to overcome the limitations.
羧肽酶A4（CPA4）是一种外肽酶，能够切割肽和蛋白质C端结构域内的肽键。它优先切割末端含有芳香族或支链氨基酸残基（如苯丙氨酸、色氨酸或亮氨酸）的肽段。CPA4最初在前列腺癌细胞中被发现，但现已明确其在全身多种组织中均有表达。其生理表达受latexin调控，后者是CPA4的一种非竞争性内源性抑制剂。然而，CPA4的过表达与多种恶性肿瘤（包括前列腺癌、胰腺癌、乳腺癌和肺癌等）的进展和侵袭性密切相关。CPA4在癌症中的作用主要归因于其对多种细胞信号通路的干扰，例如PI3K-AKT-mTOR、STAT3-ERK、AKT-cMyc、GPCR以及雌激素信号通路。CPA4对这些通路的失调可能诱导上皮-间质转化（EMT）、肿瘤侵袭和耐药性。尽管已有研究发现CPA4可调控癌症侵袭性并导致不良预后，但目前尚无系统综述全面总结CPA4在癌症中的作用。本综述简要介绍了肽酶及其分类、CPA4的发现历史、其作为肽酶的作用机制、在不同组织（包括癌症组织）中的表达情况、在各种肿瘤类型中的作用、相关分子通路及细胞过程。我们进一步探讨了当前关于CPA4与癌症关联研究的局限性，以及阻碍CPA4作为癌症侵袭性生物标志物和药物反应预测指标的挑战，并提出了若干有助于突破这些局限的未来研究策略。
Carboxypeptidase A4: A Biomarker for Cancer Aggressiveness and Drug Resistance
肿瘤(癌症)患者之家