# Carboxypeptidase A4: A Biomarker for Cancer Aggressiveness and Drug Resistance

## TL;DR

This paper reviews the role of Carboxypeptidase A4 (CPA4) in cancer aggressiveness and drug resistance, highlighting its potential as a biomarker.

## Contribution

The paper provides the first comprehensive review of CPA4's role in cancer, including its mechanisms and limitations as a biomarker.

## Key findings

- CPA4 is overexpressed in various cancers and is linked to tumor aggressiveness and drug resistance.
- CPA4 disrupts key signaling pathways like PI3K-AKT-mTOR and STAT3-ERK, contributing to cancer progression.
- Current literature on CPA4 has limitations, and future strategies are needed to validate its use as a biomarker.

## Abstract

Cancer is the second leading cause of death in developed countries and the leading cause of death in the underdeveloped world with about 20 million new diagnoses and 9.7 million deaths worldwide. Identification of biomarkers governing tumor initiation, early diagnosis, aggressiveness, or drug response and resistance is critical to reduce the cancer burden and increase patient survival. Carboxypeptidases, including CPA4, are enzymes that cleave C-terminal peptide bonds in peptides and proteins. Many of these enzymes take part in carcinogenesis and drug response. CPA4 is an exopeptidase that cleaves peptide bonds at the C-terminal domain of peptides and proteins. This enzyme is overexpressed in many cancers and often associated with cancer aggressiveness and resistance to treatment. Targeting CPA4 could serve as a novel strategy to reduce cancer burden and improve drug response.

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.