Inositol-1,4,5-trisphosphate 3-kinase-A (ITPKA) is frequently over-expressed and functions as an oncogene in several tumor types

TY - JOUR

T1 - Inositol-1,4,5-trisphosphate 3-kinase-A (ITPKA) is frequently over-expressed and functions as an oncogene in several tumor types

AU - Windhorst, Sabine

AU - Song, Kai

AU - Gazdar, Adi F

N1 - Copyright © 2017 Elsevier Inc. All rights reserved.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - At present targeted tumor therapy is based on inhibition of proteins or protein mutants that are up-regulated in tumor but not in corresponding normal cells. The actin bundling Inositol-trisphosphate 3-kinase A (ITPKA) belongs to such molecular targets. ITPKA is expressed in a broad range of tumor types but shows limited expression in normal cells. In lung and breast cancer expression of ITPKA is stimulated by gene body methylation which increases with increasing malignancy of these tumors but is not detectable in the corresponding normal tissues. Since ITPKA gene body methylation occurs early in tumor development, it could serve as biomarker for early detection of lung cancer. Detailed mechanistic studies revealed that down-regulation of ITPKA in lung adenocarcinoma cancers reduced both, tumor growth and metastasis. It is assumed that tumor growth is stimulated by the InsP3Kinase activity of ITPKA and metastasis by its actin bundling activity. A selective inhibitor against the InsP3Kinase activity of ITPKA has been identified but compounds inhibiting the actin bundling activity are not available yet. Since no curative therapy option for metastatic lung or breast tumors exist, therapies that block activities of ITPKA may offer new options for patients with these tumors. Thus, efforts should be made to develop clinical drugs that selectively target InsP3Kinase activity as well as actin bundling activity of ITPKA.

AB - At present targeted tumor therapy is based on inhibition of proteins or protein mutants that are up-regulated in tumor but not in corresponding normal cells. The actin bundling Inositol-trisphosphate 3-kinase A (ITPKA) belongs to such molecular targets. ITPKA is expressed in a broad range of tumor types but shows limited expression in normal cells. In lung and breast cancer expression of ITPKA is stimulated by gene body methylation which increases with increasing malignancy of these tumors but is not detectable in the corresponding normal tissues. Since ITPKA gene body methylation occurs early in tumor development, it could serve as biomarker for early detection of lung cancer. Detailed mechanistic studies revealed that down-regulation of ITPKA in lung adenocarcinoma cancers reduced both, tumor growth and metastasis. It is assumed that tumor growth is stimulated by the InsP3Kinase activity of ITPKA and metastasis by its actin bundling activity. A selective inhibitor against the InsP3Kinase activity of ITPKA has been identified but compounds inhibiting the actin bundling activity are not available yet. Since no curative therapy option for metastatic lung or breast tumors exist, therapies that block activities of ITPKA may offer new options for patients with these tumors. Thus, efforts should be made to develop clinical drugs that selectively target InsP3Kinase activity as well as actin bundling activity of ITPKA.

KW - Animals

KW - Biomarkers, Tumor

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Neoplasms

KW - Oncogenes

KW - Phosphotransferases (Alcohol Group Acceptor)

KW - Protein Structure, Secondary

KW - Protein Structure, Tertiary

KW - Journal Article

KW - Review

KW - Research Support, Non-U.S. Gov't

KW - Research Support, N.I.H., Extramural

U2 - 10.1016/j.bcp.2017.03.023

DO - 10.1016/j.bcp.2017.03.023

M3 - SCORING: Review article

C2 - 28377279

VL - 137

SP - 1

EP - 9

JO - BIOCHEM PHARMACOL

JF - BIOCHEM PHARMACOL

SN - 0006-2952

ER -