ARK5 Is a Tumor Invasion-Associated Factor Downstream of Akt Signaling

Abstract

AMP-activated protein kinases (AMPKs) are a class of serine/threonine protein kinases that are activated by an increase in intracellular AMP concentration. They are a sensitive indicator of cellular energy status and have been found to promote tumor cell survival during nutrient starvation. We recently identified a novel AMPK catalytic subunit family member, ARK5, whose activation is directly regulated by Akt, which, in turn, has been reported to be a key player in tumor malignancy. In this study, we attempted to determine whether ARK5 is involved in tumor malignancy under regulation by Akt. Matrigel invasion assays demonstrated that both overexpressed and endogenous ARK5 showed strong activity dependent on Akt. In addition, ARK5 expression induced activation of matrix metalloproteinase 2 (MMP-2) and MMP-9 following new expression of membrane type 1 MMP (MT1-MMP), and the MT1-MMP expression induced by ARK5 was initiated by rapamycin-sensitive signaling. In nude mice, ARK5 expression was associated with a significant increase in tumor growth and significant suppression of necrosis in tumor tissue. Interestingly, only the ARK5-overexpressing PANC-1 cell line (P/ARK) tumor showed invasion and metastasis in nude mice, although Akt was activated in tumors derived from both P/ARK and its parental cell line. We report that a novel AMPK catalytic subunit family member, ARK5, plays a key role in tumor malignancy downstream of Akt.

Rho Guanine Nucleotide Exchange Factor 5 Increases Lung Cancer Cell Tumorigenesis via MMP-2 and Cyclin D1 Upregulation

“…MMP-9 plays an important role in tumor cell invasion, metastasis, and angiogenesis (45), but no relationship was found between ARH-GEF5 and MMP-9. It should be noted that MMP expression is modulated by activation of AKT, MAPK, and NF-kB (46)(47)(48).…”

A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation

“…Evidence has shown that NUAK1 suppresses cell death induced by nutrient starvation and activation of death receptors through inhibition of caspase 8, as well as negative regulation of procaspase 6 (Suzuki et al, 2003a. Together with reports that NUAK1 is strongly associated with tumor invasion and metastasis, it has been proposed that NUAK1 is a tumor survival and tumor progression factor (Kusakai et al, 2004a, b;Suzuki et al, 2004b). The identification of NDR2 as another upstream kinase of NUAK1 upon stimulation of insulin like growth factor-1 and that hypoxia-induced tumor growth factor-b1 promotes tumor cell tolerance to glucose starvation through the Akt/ARK5 system also supported the conclusion that NUAK1 is associated with tumor malignances (Suzuki et al, 2005(Suzuki et al, , 2006.…”

SNF1/AMP-Activated Protein Kinases: Genes, Expression and Biological Role

“…This gene encodes a protein of 661 amino acid residues. ARK5, which is the fifth member of the AMPK catalytic subunit family, is a tumor malignancy-associated factor at the downstream of Akt [19]. ARK5 is a tumour cell survival and invasion-associated factor.…”

“…ARK5 is a tumour cell survival and invasion-associated factor. The activated ARK5 induces cell survival during nutrient starvation and death receptor activation, and tumor cell invasion and metastasis [18][19][20][21].…”

“…These observations support a role for SNARK as a molecular component of the cellular stress response. SNF1-like kinase 1 (NUAK1) is an AMP-activated protein kinase family member 5, ARK5, which regulates ploidy and senescence, tumour cell survival, malignancy and invasion downstream of Akt signaling, acts as an ATM kinase under the conditions of nutrient starvation [17][18][19][20]. Moreover, NUAK1 suppresses the apoptosis, induced by nutrient starvation, and death receptors via inhibition of caspase-8 and caspase-6 activation [21,22].…”