ARK5 is a tumor invasion-associated factor downstream of Akt signaling.
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.
Suzuki
Atsushi
A
Investigative Treatment Division, National Cancer Center Research Institute East, Kashiwa, Chiba 277-8577, Japan.
Lu
Jie
J
Kusakai
Gen-Ichi
G
Kishimoto
Atsuhiro
A
Ogura
Tsutomu
T
Esumi
Hiroyasu
H
D000818:Animals; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D053511:Matrix Metalloproteinase 14; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D034622:RNA Interference; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology*
C507096:Mmp14 protein, mouse; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D011494:Protein Kinases; C470845:NUAK1 protein, human; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14