CAB39L elicited an anti-Warburg effect via a LKB1-AMPK-PGC1α axis to inhibit gastric tumorigenesis

Abstract

Metabolic dysfunction is a hallmark of gastric cancer (GC). In this study, we reported the identification of Calcium Binding Protein 39-Like (CAB39L) as a novel regulator of tumor metabolism in GC. CAB39L mRNA was frequently silenced by promoter methylation in GC cell lines and tissues. Functional studies suggested that CAB39L functions as a tumor suppressor, as overexpression of CAB39L elicited suppression of multiple cancer phenotypes both in GC cells and an orthotopic mouse model; whilst its knockdown promoted tumorigenesis. Mechanistically, CAB39L interacted with LKB1-STRAD complex and induced LKB1, leading to the phosphorylation and activation of AMPKα/β. LKB1-AMPK activation in GC cell lines was tumor suppressive, as metformin (an AMPK activator) inhibited GC cell growth in the CAB39L-silenced cells. Moreover, knockdown of LKB1 reversed growth inhibitory effect of CAB39L, indicating that tumor suppression by CAB39L depended on LKB1-AMPK. RNAseq and gene set enrichment analysis revealed that CAB39L was closely correlated with oxidative phosphorylation and mitochondrial biogenesis. Consistently, CAB39L-induced p-AMPK elicited PGC1α phosphorylation and increased the expression of genes involved in mitochondrial respiration complexes. Accordingly, CAB39L reversed the Warburg effect in GC, as evidenced by enhanced oxygen consumption rate and reduced extracellular acidification rate; inversely, CAB39L knockdown promoted a metabolic shift towards the Warburg phenotype. In GC patients, CAB39L promoter hypermethylation was correlated with poor prognosis. Our data demonstrate that CAB39L is a novel tumor suppressor which suppresses tumorigenesis by promoting LKB1-AMPK-PGC1α axis, thereby preventing a metabolic shift that drives carcinogenesis. CAB39L methylation is a potential prognostic biomarker for GC patients.

<p>Preventative and Therapeutic Effects of Metformin in Gastric Cancer: A New Contribution of an Old Friend</p>

“…In addition, Li et al identified the aberrant silencing of Calcium Binding Protein 39-Like (CAB39L) in GC by promoter hypermethylation, and represented an epigenetic mechanism that contributes to metabolic dysregulation and GC development. 89 CAB39L elicited an anti-Warburg effect via a LKB1-AMPK-PGC1α axis to inhibit gastric tumorigenesis, and CAB39L-silenced GC cells exhibited an increased sensitivity to metformin. 89 …”

“… 89 CAB39L elicited an anti-Warburg effect via a LKB1-AMPK-PGC1α axis to inhibit gastric tumorigenesis, and CAB39L-silenced GC cells exhibited an increased sensitivity to metformin. 89 …”

SIRT3 elicited an anti‐Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis

“…This metabolic change provides most of the building blocks (lactate and glycolytic intermediates) required for tumor progression, despite the presence of oxygen . Therefore, it can be a potential therapeutic strategy by reversing the metabolic pattern or an anti‐Warburg effect . Mounting evidence has shown that Sirtuin‐3 (SIRT3), an NAD‐dependent deacetylase, has a dynamic role in regulating cellular metabolism .…”

Meta-analysis of genome-wide association studies and functional assays decipher susceptibility genes for gastric cancer in Chinese populations

“…In the present study, the knockout and recovery of PRKAA1 in GC cells and xenograft tumour assays in nude mice demonstrated the role of PRKAA1 in suppressing GC cell growth. Recently, it was also shown that phosphorylation and activation of AMPKα1 suppresses gastric tumourigenesis through the LKB1-AMPK-PGC1α axis 33. Notably, the use of metformin, the activator of AMPK, could reduce the risk of GC,34 but these results remain controversial in observational studies 35.…”