ATAD2 expression increases [18F]Fluorodeoxyglucose uptake value in lung adenocarcinoma via AKT-GLUT1/HK2 pathway

Abstract

[18F]Fluorodeoxyglucose (FDG) PET/CT imaging has been widely used in the diagnosis of malignant tumors. ATPase family AAA domain-containing protein 2 (ATAD2) plays important roles in tumor growth, invasion and metastasis. However, the relationship between [18F]FDG accumulation and ATAD2 expression remains largely unknown. This study aimed to investigate the correlation between ATAD2 expression and [18F]FDG uptake in lung adenocarcinoma (LUAD), and elucidate its underlying molecular mechanisms. The results showed that ATAD2 expression was positively correlated with maximum standardized uptake value (SUV max ), total lesion glycolysis (TLG), glucose transporter type 1 (GLUT1) expression and hexokinase2 (HK2) expression in LUAD tissues. In addition, ATAD2 knockdown significantly inhibited the proliferation, tumorigenicity, migration, [18F]FDG uptake and lactate production of LUAD cells, while, ATAD2 overexpression exhibited the opposite effects. Furthermore, ATAD2 modulated the glycometabolism of LUAD via AKT-GLUT1/HK2 pathway, as assessed using LY294002 (an inhibitor of PI3K/AKT pathway). In summary, to explore the correlation between ATAD2 expression and glycometabolism is expected to bring good news for anti-energy metabolism therapy of cancers.

SKA3 promotes lung adenocarcinoma metastasis through the EGFR–PI3K–Akt axis

“…We further assessed the role of SKA3 in EMT processes [22][23][24][25] but no associations were observed. Upon further analysis, we found that AKT activation strongly correlated with SKA3 expression, and that the expression of MMP following SKA3 silencing decreased in a manner that could be rescued by exogenous AKT overexpression, suggestive that SKA3 influences MMP-2, -7 and -9 to promote of LUAD occurrence and development [26][27][28][29][30][31][32]. These data further suggested that the selective modulation of SKA3 during EGFR-PI3K-AKT signaling in LUADs leads to EGF modulation, with no effects on HGF-signaling.…”

ATPase family AAA domain-containing protein 2 (ATAD2): From an epigenetic modulator to cancer therapeutic target

“…Furthermore, ATAD2 promotes tumor progression as a coactivator of the hormone-induced nuclear receptors ERα and androgen receptor (AR), E2Fs and c-Myc 38 . In lung adenocarcinoma and gastric cancer, ATAD2 could promote cell proliferation via the phosphatidylinositol 3 kinase (PI3K) / AKT pathway and the retinoblastoma tumor suppressor protein (Rb)-E2F-cMyc signaling 39 , 40 . While in lung adenocarcinoma, the knockdown of ATAD2 affects glucose metabolism in cancer cells by regulating [18F] FDG uptake and lactate production through the AKT-GLUT1 / HK2 pathway 39 .…”

“…In lung adenocarcinoma and gastric cancer, ATAD2 could promote cell proliferation via the phosphatidylinositol 3 kinase (PI3K) / AKT pathway and the retinoblastoma tumor suppressor protein (Rb)-E2F-cMyc signaling 39 , 40 . While in lung adenocarcinoma, the knockdown of ATAD2 affects glucose metabolism in cancer cells by regulating [18F] FDG uptake and lactate production through the AKT-GLUT1 / HK2 pathway 39 . In addition, silencing ATAD2 also inhibits the growth and colony formation ability of esophageal squamous cell carcinoma (ESCC) cells, and significantly inhibits ESCC tumor growth in vitro 41 .…”

Tumor-Promoting ATAD2 and Its Preclinical Challenges

“…The study further pointed out that this was caused by ATAD2 promoting LUAD glucose metabolism via the AKT-GLUT1/HK2 pathway. In addition, ATAD2 also promotes the proliferation, tumorigenicity, and migration of lung cancer cells utilizing the PI3K/AKT pathway [ 47 ]. ATAD2 knockdown inhibited the migration, invasion, stem cell-like properties, and mitochondrial reactive oxygen species (mtROS) production of lung cancer cells.…”

“…The integrity of HIF-1α/ATAD2 triggered by CIH may determine the aggressiveness of lung cancer through the interaction of mtROS and stemness in lung cancer cells [ 48 ]. ATAD2 overexpression is closely associated with positive LUAD lymph node metastasis, poor tumor differentiation, advanced disease stage, and prognosis, and it is an individual marker of adverse prognosis after surgical resection of lung adenocarcinoma [ 5 , 47 , 126 , 127 ].…”