HGK promotes metastatic dissemination in prostate cancer (original) (raw)
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2008
Prostate cancer is the second leading cause of cancer-related deaths in men. Although initially effective, hormonal ablation therapy is not curative and invariably leads to emergence of androgenindependent disease which does not respond to existing therapeutics. Activation of MAP kinase signaling pathway has been implicated in advanced and androgen-independent prostate cancers, although formal genetic proof has been lacking. Taking advantage of a unique androgen-insensitive transgene promoter system, we developed a novel genetically-engineered mouse (GEM) model of invasive prostate adenocarcinoma whereby an activating mutation of BRAF – a mutation found in ~10% of human prostate tumors – has been targeted to the basal progenitor compartment of the prostate gland. These GEM mice developed prostate gland hyperplasia with progression to AKT-independent invasive adenocarcinoma that readily transitions to androgen-independent state upon castration, thus providing unequivocal genetic proo...
Molecular mechanisms of metastasis in prostate cancer
Asian Journal of Andrology, 2008
Prostate cancer (PCa) preferentially metastasizes to the bone marrow stroma of the axial skeleton. This activity is the principal cause of PCa morbidity and mortality. The exact mechanism of PCa metastasis is currently unknown, although considerable progress has been made in determining the key players in this process. In this review, we present the current understanding of the molecular processes driving PCa metastasis to the bone.
The TLK1-MK5 axis regulates motility, invasion, and metastasis of prostate cancer cells
ABSTRACTBackgroundMetastatic dissemination of prostate cancer (PCa) accounts for majority of PCa related deaths. However, the exact mechanism of PCa cell spread is still unknown. We uncovered a novel interaction between two unrelated promotility factors, tousled-like kinase 1 (TLK1) and MAPK-activated protein kinase 5 (MK5), which initiates a signaling cascade promoting metastasis. In PCa, TLK1-MK5 signaling might be crucial as androgen deprivation therapy (ADT) leads to increased expression of both TLK1 and MK5 in metastatic patients, but in this work, we directly investigated the motility, invasive, and metastatic capacity of PCa cells following impairment of the TLK1>MK5 axis.ResultsWe conducted scratch wound repair and 3D invasion assays with LNCaP and PC3 cells to determine if TLK1 and MK5 can regulate motility and invasion. Both genetic depletion and pharmacologic inhibition of TLK1 and MK5 resulted in reduced migration and invasion through a Matrigel plug. We further eluci...
PRK1/PKN1 controls migration and metastasis of androgen-independent prostate cancer cells
Oncotarget, 2014
The major threat in prostate cancer is the occurrence of metastases in androgen-independent tumor stage, for which no causative cure is available. Here we show that metastatic behavior of androgen-independent prostate tumor cells requires the protein-kinase-C-related kinase (PRK1/PKN1) in vitro and in vivo. PRK1 regulates cell migration and gene expression through its kinase activity, but does not affect cell proliferation. Transcriptome and interactome analyses uncover that PRK1 regulates expression of migration-relevant genes by interacting with the scaffold protein sperm-associated antigen 9 (SPAG9/JIP4). SPAG9 and PRK1 colocalize in human cancer tissue and are required for p38-phosphorylation and cell migration. Accordingly, depletion of either ETS domain-containing protein Elk-1 (ELK1), an effector of p38-signalling or p38 depletion hinders cell migration and changes expression of migration-relevant genes as observed upon PRK1-depletion. Importantly, a PRK1 inhibitor prevents m...
Role of MAP kinase in tumor progression and invasion
Cancer metastasis reviews, 2003
Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway is a frequent event in tumorigenesis. MAPKs have been implicated in cell migration, proteinase-induction, regulation of apoptosis, and angiogenesis, events that are essential for successful completion of metastasis. In this review, we discuss the potential role that MAPKs play in metastasis by regulating cell migration, proteinase-induction and apoptosis.
GRK3 is essential for metastatic cells and promotes prostate tumor progression
Proceedings of the National Academy of Sciences, 2014
Significance Although the majority of cancer-related deaths are consequences of metastatic dissemination, the molecular and cellular forces that drive tumor cell dispersion are still poorly understood. To help identify new regulators that play critical roles in these processes, we screened for human kinases that are important for continued survival of metastatic cells. One kinase identified from these screens, the G-protein–coupled receptor kinase 3 (GRK3; or β-adrenergic receptor kinase 2), was found to have a key role in promoting prostate tumor growth and metastasis in mouse models through enhancing angiogenesis. Notably, GRK3 is overexpressed in human prostate metastatic tumors. Further studies on GRK3 and its pathways promise to expand our knowledge of cancer metastasis and also yield new cancer therapeutic targets.
MAP Kinases and Prostate Cancer
Prostate Cancer - From Bench to Bedside, 2011
One of the most relevant aspects in cell death regulation is the signaling of apoptosis by serine/threonine kinases, a broad category of kinases that includes, among others, the mitogen-activated protein kinases (MAPKs) (Cross et al., 2000; Khlodenko & Birtwistle, 2009). The three main members that integrate the MAPK family in mammalian cells are: the stressactivated protein kinase c-Jun NH 2-terminal kinases (JNK), the stress-activated protein kinase 2 (SAPK2, p38), and the extracellular signal-regulated protein kinases (ERK1/2, p44/p42) (Fig. 1). In addition, other less well-characterized MAPK pathways exist, such as the extracellular regulated kinase 5 (ERK5) pathway (Hayashi &Lee, 2004; Junttila & Li, 2008) (Fig. 1). Albeit with multiple exceptions, JNK and ERK5 are generally associated with apoptosis induction; while ERK1/2 are generally associated to mitogenesis, and therefore inversely related to apoptosis (
Role of MAP kinase in tumor progression and invasion : Protein kinases
Cancer Metastasis Reviews, 2003
Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway is a frequent event in tumorigenesis. MAPKs have been implicated in cell migration, proteinaseinduction, regulation of apoptosis, and angiogenesis, events that are essential for successful completion of metastasis. In this review, we discuss the potential role that MAPKs play in metastasis by regulating cell migration, proteinase-induction and apoptosis.
Molecular determinants of prostate cancer metastasis
Oncotarget, 2015
Metastatic cancer remains largely incurable and fatal. The general course of cancer, from the initiation of primary tumor formation and progression to metastasis, is a multistep process wherein tumor cells at each step must display specific phenotypic features. Distinctive capabilities required for primary tumor initiation and growth form the foundation, and sometimes may remain critical, for subsequent metastases. These phenotypic features must remain easily malleable during the acquisition of additional capabilities unique and essential to the metastatic process such as dissemination to distant tissues wherein tumor cells interact with foreign microenvironments. Thus, the metastatic phenotype is a culmination of multiple genetic and epigenetic alterations and subsequent selection for favorable traits under the pressure of ever-changing tumor microenvironments. Although our understanding of the molecular programs that drive cancer metastasis are incomplete, increasing evidence suggests that successful metastatic colonization relies on the dissemination of cancer stem cells (CSCs) with tumor-regenerating capacity and adaptive programs for survival in distant organs. In the past 2-3 years, a myriad of novel molecular regulators and determinants of prostate cancer metastasis have been reported, and in this Perspective, we comprehensively review this body of literature and summarize recent findings regarding cell autonomous molecular mechanisms critical for prostate cancer metastasis.