Low molecular weight protein tyrosine phosphatase (LMWPTP) upregulation mediates malignant potential in colorectal cancer.

Elmer Hoekstra,Roberta R Ruela-De-Sousa,Liudmila L Kodach,Maikel P Peppelenbosch,Asha M Das,C Janneke Van Der Woude,Timo L.M Ten Hagen,Carmen V Ferreira,Gwenny M Fuhler,James C Hardwick

doi:10.18632/oncotarget.3224

Abstract

Phosphatases have long been regarded as tumor suppressors, however there is emerging evidence for a tumor initiating role for some phosphatases in several forms of cancer. Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP; acid phosphatase 1 [ACP1]) is an 18 kDa enzyme that influences the phosphorylation of signaling pathway mediators involved in cancer and is thus postulated to be a tumor-promoting enzyme, but neither unequivocal clinical evidence nor convincing mechanistic actions for a role of LMWPTP have been identified. In the present study, we show that LMWPTP expression is not only significantly increased in colorectal cancer (CRC), but also follows a step-wise increase in different levels of dysplasia. Chemical inhibition of LMWPTP significantly reduces CRC growth. Furthermore, downregulation of LMWPTP in CRC leads to a reduced migration ability in both 2D- and 3D-migration assays, and sensitizes tumor cells to the chemotherapeutic agent 5-FU. In conclusion, this study shows that LMWPTP is not only overexpressed in colorectal cancer, but it is correlated with the malignant potential of this cancer, suggesting that this phosphatase may act as a predictive biomaker of CRC stage and represents a rational novel target in the treatment of this disease.

Highlights

Colorectal cancer (CRC) is one of the most common forms of cancer in the Western world
This study shows that Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP) is overexpressed in colorectal cancer, but it is correlated with the malignant potential of this cancer, suggesting that this phosphatase may act as a predictive biomaker of CRC stage and represents a rational novel target in the treatment of this disease
We examined whether the increased ACP1 expression corresponds to increased protein levels of LMWPTP in CRC samples

Summary

Introduction

Colorectal cancer (CRC) is one of the most common forms of cancer in the Western world. Around 20% of the CRC patients already present with metastatic disease, dropping the 5-year survival rate from 90% to a dramatic 12% [2]. For this reason, treatments focusing on the prevention of this progression into the metastatic state are urgently called for. Like many neoplasms, disturbed protein phosphorylation patterns, indicating imbalanced kinase and/or phosphatase activities, are often observed in colorectal cancer [3]. Despite the fact that these drugs have shown some promising results [5, 6], there is still a need for www.impactjournals.com/oncotarget new, additional, classes of molecules as potential targets

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