Abstract
Amplification or over-expression of an activated Cdc42-associated kinase 1 (ACK1) gene is common in breast, lung and ovarian cancers. However, little is known about the role of ACK1 in gastric tumorigenesis. Here, we found that DNA copy numbers of the ACK1 gene and its mRNA expression levels were significantly increased in gastric cancer (GC) compared to normal gastric tissues. Additionally, silencing ACK1 inhibited GC cell proliferation and colony formation, induced G2/M arrest and cellular apoptosis in vitro, and suppressed tumor growth in vivo. Gene Ontology annotation revealed that 147 differential proteins regulated by ACK1 knockdown were closely related with cellular survival. A cell cycle regulator, ecdysoneless homolog (ECD), was found to be significantly down-regulated by ACK1 knockdown. Silencing of ECD inhibited colony formation and induced G2/M arrest and cell apoptosis, which is similar to the effects of ACK1 knockdown. Silencing of ECD did not further enhance the effects of ACK1 knockdown on G2/M arrest and apoptosis, while silencing of ECD blocked the enhancement of colony formation by ACK1 over-expression. Over-expression of ACK or ECD promoted the ubiquitination of tumor suppressor p53 protein and decreased p53 levels, while silencing of ACK1 or ECD decreased the p53 ubiquitination level and increased p53 levels. Silencing of ECD attenuated the ubiquitination enhancement of p53 induced by ACK1 over-expression. Collectively, we demonstrate that amplification of ACK1 promotes gastric tumorigenesis by inducing an ECD-dependent ubiquitination degradation of p53.
Highlights
Gastric cancer (GC) is one of the most common malignancies in the world, and it has poor prognosis and limited treatment options, accounting for 10% of all cancer-related deaths and 8% of all cancer cases [1]
Our previous study showed that associated kinase 1 (ACK1) protein levels and ACK1 phosphorylation at Tyr 284 were frequently elevated in GC and associated with poor survival in GC patients [16]
To further investigate whether the ACK1 gene is amplified in GC tissues, ACK1 DNA copy numbers in gastric adenocarcinoma and normal gastric tissues were analyzed using two DNA datasets deposited in the Oncomine database
Summary
Gastric cancer (GC) is one of the most common malignancies in the world, and it has poor prognosis and limited treatment options, accounting for 10% of all cancer-related deaths and 8% of all cancer cases [1]. The gene amplification of activated Cdc42-associated kinase 1 (ACK1) is common in breast, lung and ovarian cancers [5,6,7,8]. ACK1 was originally identified as a non-receptor tyrosine kinase that bound to the GTP-Cdc complex and inhibited its GTPase activity [9]. Over-expression of ACK1 is associated with cancer progression and metastasis in breast cancer, prostate cancer, non-small-cell lung cancer and hepatocellular carcinoma [5, 10,11,12,13,14,15]. Our previous study showed that ACK1 is significantly up-regulated in GC compared to adjacent gastric tissues and is associated with a poor prognosis in GC patients [16]. The impact of ACK1 on GC tumorigenesis and its molecular mechanisms in GC have not been elucidated
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