Lemur Tyrosine Kinase 2, a novel target in prostate cancer therapy

Abstract

Progression from early forms of prostate cancer to castration-resistant disease is associated with an increase in signal transduction activity. The majority of castration-resistance cancers persist in the expression of the androgen receptor (AR), as well as androgen-dependent genes. The AR is regulated not only by it associated steroid hormone, but also by manifold regulatory and signaling molecules, including several kinases. We undertook evaluation of the role of Lemur Tyrosine Kinase 2 (LMTK2) in modulating AR activity, as several Genome Wide Association Studies (GWAS) have shown a marked association of LMTK2 activity with the development of prostate cancer. We confirm that not only is LMTK2 mRNA reduced in prostate cancer tissue, but also LMTK2 protein levels are markedly diminished. Knockdown of LMTK2 protein in prostate cell lines greatly increased the transcription of androgen-responsive genes. In addition, LMTK2 knockdown led to an increase in prostate cancer stem cell populations in LNCaP cells, indicative of increased tumorogenicity. Using multiple approaches, we also demonstrate that LMTK2 interacts with the AR, thus putting LMTK2 as a component of a signaling complex modulating AR activity. Our finding that LMTK2 is a negative regulator of AR activity defines a novel cellular pathway for activation of AR-responsive genes in castrate resistant-prostate cancer. Moreover, pharmacologic manipulation of LMTK2 activity will provide a novel therapeutic target for more effective treatments for patients with castrate-resistant prostate cancer.

Lemur Tyrosine Kinase 2 (LMTK2) Level Inversely Correlates with Phospho-Tau in Neuropathological Stages of Alzheimer’s Disease

“…Because neurons are terminally differentiated cells it is possible that certain noxious stimuli which cause uncontrolled proliferation in other organs result in aberrant cell cycle re-entry with degenerative changes and apoptosis in nerve cells [42][43][44][45][46][47]. The role of LMTK2 has been investigated in several malignancies, particularly in prostate cancer [48][49][50][51]. Harries et al reported reduced LMTK2 expression in prostate adenocarcinoma, compared to benign prostate hyperplasia [50].…”

Mechanisms of tumor cell resistance to the current targeted-therapy agents

“…Several kinds of research have shown that treatment failure in several tumors has been attributed to the presence of CSCs [16][17][18][19]. These cells are naturally extremely resistant to different therapeutic approaches (Fig.…”

Kinase Modulation of Androgen Receptor Signaling: Implications for Prostate Cancer

“…For example, phosphorylation of AR by CDK1 and CDK9 can regulate the transcriptional activity of AR by regulating AR expression or transactivation respectively [28, 29] . Furthermore, kinases like LMTK2 and Lyn have also been implicated in manipulating AR signaling pathways and support the progression of prostate cancer to advanced androgen-independent stages of prostate cancer [30, 31] . Understanding, detailed molecular mechanisms and the role of the various phosphorylated AR species holds the key to identifying phosphorylation sites that could serve as a potential therapeutic drug targets for patients with prostate cancer and CRPC.…”

“…Furthermore, a comparative study of LMTK2 mRNA levels in tissue from patients prostate cancer and Benign Prostatic Hyperplasia (BPH) revealed a markedly reduced level of LMTK2 in prostate cancer patients [53] . Recently, using immunohistochemistry we demonstrated that LMTK2 protein levels are also down-regulated in human prostate cancer tissue in comparison to adjacent non-cancerous tissue or tissue from patients with BPH [31] . Furthermore, we identified AR to be a binding partner of LMTK2 in prostate cancer epithelial cells.…”