Ajuba overexpression regulates mitochondrial potential and glucose uptake through YAP/Bcl-xL/GLUT1 in human gastric cancer.

Abstract

Ajuba dysregulation has been reported in several human cancers. However, its expression patterns and biological roles in human gastric cancers have not yet been characterized. In the current study, we found that Ajuba protein was increased in gastric cancer tissues and in cell lines. High Ajuba expression positively correlated with the tumor-node-metastasis (TNM) stage, lymph node metastasis and poor prognosis. The Cancer Genome Atlas (TCGA) and Oncomine microarray data mining also suggested that Ajuba mRNA upregulation in gastric cancer tissues. We used SGC-7901 and NCI-N87 cell lines for Ajuba overexpression and siRNA knockdown respectively. MTT and colony formation assays indicated that Ajuba overexpression increased proliferation rate and colony formation ability while Ajuba siRNA inhibited proliferation rate and colony formation ability. AnnexinV and JC1 staining showed that Ajuba downregulated cisplatin induced apoptosis while it upregulated mitochondrial membrane potential. Ajuba overexpression also inhibited caspase-3 and PARP cleavage, while Ajuba depletion showed the opposite effects. Notably, Ajuba enhanced glucose metabolism by upregulating glucose uptake, glucose consumption, lactate production and ATP production. We further revealed that Ajuba positively regulated cyclin D1, Bcl-xL and GLUT1 at both mRNA and protein levels. Analysis of TCGA dataset revealed that there were positive correlations between Ajuba and cyclin D1, Bcl-xL, GLUT1 at the mRNA levels. Further investigation demonstrated that Ajuba overexpression inhibited Hippo signaling by upregulating YAP protein expression. Depletion of YAP by siRNA abolished the effect of Ajuba on cyclin D1, Bcl-xL and GLUT1. Together, our study showed that Ajuba was overexpressed in human gastric cancers, where it increased cell growth and chemoresistance. Our data also identified novel roles of Ajuba in gastric cancer progression involving regulating glucose uptake and mitochondrial function through the YAP-GLUT1/Bcl-xL axis, making it a potential therapeutic target.

• Authors: Haiying Li, Lin Fu, Bin Liu, Xiumin Lin, Qianze Dong, Enhua Wang
• Journal: Gene (Gene) Vol. 693 Pg. 16-24 (Apr 20 2019) ISSN: 1879-0038 [Electronic] Netherlands
• PMID: 30690182 (Publication Type: Journal Article)
• Copyright: Copyright © 2019. Published by Elsevier B.V.

Chemical References

• AJUBA protein, human
• Adaptor Proteins, Signal Transducing
• BCL2L1 protein, human
• Glucose Transporter Type 1
• LIM Domain Proteins
• Phosphoproteins
• SLC2A1 protein, human
• Transcription Factors
• YAP-Signaling Proteins
• YAP1 protein, human
• bcl-X Protein
• Glucose
• Cisplatin

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Adult
• Aged
• Aged, 80 and over
• Apoptosis (genetics)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cisplatin (pharmacology)
• Drug Resistance, Neoplasm (genetics)
• Female
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• Glucose (metabolism)
• Glucose Transporter Type 1 (metabolism)
• Humans
• LIM Domain Proteins (genetics, metabolism)
• Male
• Membrane Potential, Mitochondrial (physiology)
• Middle Aged
• Mitochondria (genetics, metabolism)
• Phosphoproteins (metabolism)
• Signal Transduction (drug effects)
• Stomach Neoplasms (genetics, metabolism)
• Transcription Factors
• YAP-Signaling Proteins
• bcl-X Protein (metabolism)