ARK5 promotes glioma cell invasion, and its elevated expression is correlated with poor clinical outcome

Lu, Shaoying; Niu, Na; Guo, Hua; Tang, Jin‐Bao; Guo, Wei; Liu, Zhijun; Shi, Lihong; Sun, Tiantian; Zhou, Fenghua; Liu, Hongli; Zhang, Jin; Zhang, Baogang

doi:10.1016/j.ejca.2012.09.018

Cited by 51 publications

(60 citation statements)

References 40 publications

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“…Ark5 is a member of the AMPK family and found to be directly phosphorylated and activated by Akt to prevent cell death. It was reported that Ark5-mediated mTOR phosphorylation induced by IGF-1 plays a key role in tumor malignancy and transient RNAi-mediated ARK5 knockdown caused significant reductions in cell proliferation and brain invasion in a glioma xenograft mouse model (17-20). CDK4 has been shown to be responsible for hyperphosphorylation of tumor suppressor protein Rb releasing its inhibition on G1/S cell cycle progression through activation of the transcription factor E2F (21).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Pharmacological Evaluation of a Novel Multiple Kinase Inhibitor, ON123300, in Brain Tumor Models

Zhang

Zhou

et al. 2014

Molecular Cancer Therapeutics

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ON123300 is a low molecular weight multi-kinase inhibitor identified through a series of screens that supported further analyses for brain tumor chemotherapy. Biochemical assays indicated ON123300 was a strong inhibitor of Ark5 and CDK4 as well as growth factor receptor tyrosine kinases such as Beta-type platelet-derived growth factor receptor [PDGFRβ]. ON123300 inhibited U87 glioma cell proliferation with an IC50 = 3.4 ± 0.1 μM and reduced phosphorylation of Akt, yet it also unexpectedly induced Erk activation; both in a dose- and time-dependent manner that subsequently was attributed to relieving Akt-mediated C-Raf S259 inactivation and activating a p70S6K initiated PI3K negative feedback loop. Co-treatment with the EGFR inhibitor gefitinib [GFN] produced synergistic cytotoxic effects. Pursuant to the in vitro studies, in vivo pharmacokinetic [PK] and pharmacodynamic [PD] studies of ON123300 were completed in mice bearing intracerebral U87 tumors following IV doses of 5 mg/kg and 25 mg/kg alone, and also at the higher dose concurrently with GFN. ON123300 showed high brain and brain tumor accumulation based on brain partition coefficient values of at least 2.5. Consistent with the in vitro studies, single agent ON123300 caused a dose-dependent suppression of phosphorylation of Akt as well as activation of Erk in brain tumors, whereas addition of GFN to the ON123300 regimen significantly enhanced p-Akt inhibition and prevented Erk activation. In summary, ON123300 demonstrated favorable PK characteristics and future development for brain tumor therapy would require use of combinations, such as GFN, that mitigated its Erk activation and enhanced its activity.

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Section: Introductionmentioning

confidence: 99%

Preclinical Pharmacological Evaluation of a Novel Multiple Kinase Inhibitor, ON123300, in Brain Tumor Models

Zhang

Zhou

et al. 2014

Molecular Cancer Therapeutics

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“…Akt, one of the most commonly pathways in various types of cancers, is regarded as an important element in facilitating cancer cells proliferation, oncogenesis, survival, invasion and metastasis [14], and ARK5 is a crucial effector of these actions of Akt. Notably, recent investigations reveal that ARK5 is a critical molecule in promoting the invasion and metastasis of cancer cells in certain human malignancies [15, 16], including those of hepatocellular carcinoma [17], colorectal cancer [18], glioma [19] and non-small cell lung cancer [20]. More importantly, the high expression level of ARK5 in cancer tissues correlates with advanced clinical stage, enhanced metastatic potential and shortened patient survival [17, 19, 20], indicating that ARK5 may be a valuable prognostic marker in a variety of human malignancies.…”

Section: Introductionmentioning

confidence: 99%

“…Notably, recent investigations reveal that ARK5 is a critical molecule in promoting the invasion and metastasis of cancer cells in certain human malignancies [15, 16], including those of hepatocellular carcinoma [17], colorectal cancer [18], glioma [19] and non-small cell lung cancer [20]. More importantly, the high expression level of ARK5 in cancer tissues correlates with advanced clinical stage, enhanced metastatic potential and shortened patient survival [17, 19, 20], indicating that ARK5 may be a valuable prognostic marker in a variety of human malignancies. More recently, an interesting finding demonstrates that ARK5 expression is closely associated with more aggressive cancer characteristics and a poor prognosis for patients with GC [21], despite its actual role and the underlying mechanism involved in GC invasion and metastasis have not yet been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Knockdown of ARK5 Expression Suppresses Invasion and Metastasis of Gastric Cancer

Chen¹,

Liu²,

Xu³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Gastric cancer (GC) is a common and lethal malignancy, and AMP-activated protein kinase-related kinase 5 (ARK5) has been discovered to promote cancer metastasis in certain types of cancer. In this study, we explored the role of ARK5 in GC invasion and metastasis. Methods: ARK5 and epithelial-mesenchymal transition (EMT)-related markers were determined by immunohistochemistry and western blot in GC specimens. Other methods including stably transfected against ARK5 into SGC7901 and AGS cells, western blot, migration and invasion assays in vitro and nude mice tumorigenicity in vivo were also employed. Results: The results demonstrated that ARK5 expression was increased and positively correlated with metastasis, EMT-related markers and poor prognosis in patients with GC. Knockdown of ARK5 expression remarkably suppressed GC cells invasion and metastasis via regulating EMT, rather than proliferation in vitro and in vivo. And knockdown of ARK5 expression in GC cells resulted in the down-regulation of the mTOR/p70S6k signals, Slug and SIP1. Conclusion: The elevated ARK5 expression was closely associated with cancer metastasis and patient survival, and it seemed to function in GC cells migration and invasion via EMT alteration, together with the alteration of the mTOR/p70S6k signals, Slug and SIP1, thus providing a potential therapeutic target for GC.

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“…In addition, in these mice, phosphorylated MLC2, F-actin and cortactin fail to effectively concentrate at apical cell surfaces, indicating that NUAK kinases may contribute to apical constriction and cell shape control. NUAK1 and NUAK2 functions have been studied in human (Lu et al, 2013, mouse (Ohmura et al, 2012), D. melanogaster (Amin et al, 2009) and C. elegans (Hoppe et al, 2010). In this article, we report on NUAK1 and NUAK2 mRNA expression in early chick embryos.…”

mentioning

confidence: 99%

“…sis for glioma (Lu et al, 2013). Recently, it was shown to favor an invasive phenotype in human breast cancer which also depended on AKT signaling.…”

mentioning

confidence: 99%

Analysis of NUAK1 and NUAK2 expression during early chick development reveals specific patterns in the developing head

Bekri¹,

Billaud²,

Thélu³

2014

Int. J. Dev. Biol.

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Several human diseases are associated with the NUAK1 and NUAK2 genes. These genes encode kinases, members of the AMPK-related kinases (ARK) gene family. Both NUAK1 and NUAK2 are known targets of the serine threonine kinase LKB1, a tumor suppressor involved in regulating cell polarity. While much is known about their functions in disease, their expression pattern in normal development has not been extensively studied. Here, we present the expression patterns for NUAK1 and NUAK2 in the chick during early-stage embryogenesis, until day 3 (Hamburger and Hamilton stage HH20). Several embryonic structures, in particular the nascent head, showed distinct expression levels. NUAK1 expression was first detected at stage HH6 in the rostral neural folds. It was then expressed (HH7-11) throughout the encephalalon, predominantly in the telencephalon and mesencephalon. NUAK1 expression was also detected in the splanchnic endoderm area at HH8-10, and in the vitellin vein derived from this area, but not in the heart. NUAK2 expression was first detected at stage HH6 in the neural folds. It was then found throughout the encephalon at stage HH20. Particular attention was paid in this study to the dorsal ectoderm at stages HH7 and HH8, where a local deficit or accumulation of NUAK2 mRNA were found to correlate with the direction of curvature of the neural plate. This is the first description of NUAK1 and NUAK2 expression patterns in the chick during early development; it reveals non-identical expression profiles for both genes in neural development. KEY WORDS: NUAK, chick embryo, in situ hybridizationNUAK1 and NUAK2 are members of the novel (Nua) kinases family. Their alternative names include: ARK5 or OMPHK1 for NUAK1; and SNARK or OMPHK2 for NUAK2. They are two of the fourteen known substrates of the serine threonine kinase LKB1 and are part of the AMPK-related protein kinase family (ARK) (Al-Hakim et al., 2005, Hardie and Alessi, 2013, Manning et al., 2002, Suzuki et al., 2003. AMPK is a mammalian homolog of sucrose non-fermentable protein kinase (SNF-1); it is a member of a serine/threonine protein kinase family. Unlike AMPK, which is activated under various stress conditions resulting in decreased ATP concentrations (Scott et al., 2007), ARKs do not have AMP: ATP ratio-sensitive regulatory subunits. Thus, they do not directly participate in adaptive responses to energy balance (Al-Hakim et al., 2005).NUAK1 was first described as supporting AKT-dependent cell survival during nutrient starvation (Suzuki et al., 2003), and has been shown to induce p53 phosphorylation (Hou et al., 2011). NUAK1 expression is now known to be closely associated with metastases, colorectal cancer and is an indicator of poor prognoInt. J. Dev. Biol. 58: 379-384 (2014) sis for glioma (Lu et al., 2013). Recently, it was shown to favor an invasive phenotype in human breast cancer which also depended on AKT signaling. This may be linked to its role in cell adhesion through phosphorylation of the regulatory sub-unit of the myosin light chain 2 (MLC...

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ARK5 promotes glioma cell invasion, and its elevated expression is correlated with poor clinical outcome

Cited by 51 publications

References 40 publications

Preclinical Pharmacological Evaluation of a Novel Multiple Kinase Inhibitor, ON123300, in Brain Tumor Models

Preclinical Pharmacological Evaluation of a Novel Multiple Kinase Inhibitor, ON123300, in Brain Tumor Models

Knockdown of ARK5 Expression Suppresses Invasion and Metastasis of Gastric Cancer

Analysis of NUAK1 and NUAK2 expression during early chick development reveals specific patterns in the developing head

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