PGC-1α Regulates Cell Proliferation, Migration, and Invasion by Modulating Leucyl-tRNA Synthetase 1 Expression in Human Colorectal Cancer Cells

Abstract

Although mounting evidence has demonstrated that peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) can promote tumorigenesis, its role in cancer remains controversial. To find potential target molecules of PGC-1α, GeneFishingTM DEG (differentially expressed genes) screening was performed using stable HEK293 cell lines expressing PGC-1α (PGC-1α-HEK293). As results, leucyl-tRNA synthetase 1 (LARS1) was upregulated. Western blot analysis showed that LARS1 was increased in PGC-1α overexpressed SW480 cells but decreased in PGC-1α shRNA knockdown SW620 cells. Several studies have suggested that LARS1 can be a potential target of anticancer agents. However, the molecular network of PGC-1α and LARS1 in human colorectal cancer cells remains unclear. LARS1 overexpression enhanced cell proliferation, migration, and invasion, whereas LARS1 knockdown reduced them. We also observed that expression levels of cyclin D1, c-Myc, and vimentin were regulated by LARS1 expression. We aimed to investigate whether effects of PGC-1α on cell proliferation and invasion were mediated by LARS1. Our results showed that PGC-1α might modulate cell proliferation and invasion by regulating LARS1 expression. These results suggest that LARS1 inhibitors might be used as anticancer agents in PGC-1α-overexpressing colorectal cancer. Further studies are needed in the future to clarify the detailed molecular mechanism by which PGC-1α regulates LARS1 expression.

Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family in physiological and pathophysiological process and diseases

“…282 Another downstream pathway of PGC-1α in CRC is AKT/GSK-3β/β-catenin. 283,284 PGC-1α knockdown downregulates the expression of p-AKT, p-GSK-3β, β-catenin, N-cadherin and mitigates cell proliferation, migration, and invasion, while the opposite effects are observed in PGC-1α overexpressing cells. 284 Moreover, PGC-1α can act as a downstream molecule of SIRT3 in CRC.…”

From metabolism to malignancy: the multifaceted role of PGC1α in cancer

“…Functionally, PGC1α plays a crucial role in enhancing mitochondrial biogenesis and oxidative phosphorylation, thereby reprogramming the metabolism to support cell proliferation, growth, and survival ( 23 , 30 , 37 ). Particularly under hypoxic conditions, PGC1α exerts an antioxidant effect to shield cancer cells from accumulation of ROS ( 23 ).…”

“…It promotes the activation of the AKT/GSK-3β pathway through physical interactions with AKT, although the exact mechanisms remain undefined ( 39 ). Additionally, PGC1α boosts leucyl-tRNA synthetase 1 (LARS1) expression, further stimulating AKT/GSK-3β signaling ( 37 ).WNT/β-catenin pathway can also be activated by PGC1α, which promotes CRC cell proliferation and inhibits apoptosis ( 37 , 39 ). PGC1α activates the epithelial-mesenchymal transition (EMT) pathway by upregulating transcription factors like Snail, Slug, and Twist ( 37 , 39 ), thereby facilitating cancer cell migration and invasion.…”

“…Additionally, PGC1α boosts leucyl-tRNA synthetase 1 (LARS1) expression, further stimulating AKT/GSK-3β signaling ( 37 ).WNT/β-catenin pathway can also be activated by PGC1α, which promotes CRC cell proliferation and inhibits apoptosis ( 37 , 39 ). PGC1α activates the epithelial-mesenchymal transition (EMT) pathway by upregulating transcription factors like Snail, Slug, and Twist ( 37 , 39 ), thereby facilitating cancer cell migration and invasion. Recent findings have also indicated that PGC1α can orchestrate lactate oxidation, further promoting the migration and invasion of normoxic CSCs in CRC ( 29 ).…”

LARS1 is a Prognostic Biomarker and Exhibits a Correlation with Immune Infiltrates in Hepatocellular Carcinoma

“…LARS1 also controls protein synthesis, metabolism, autophagy, and cell growth by regulating the mechanistic target of rapamycin complex 1 (mTORC1) pathway. 11 LARS1 has been illustrated to play essential roles and might be potential therapy targets in various tumors, like Colon cancer, 12 Lung cancer, 13 , 14 Osteosarcoma 15 and breast cancer. 16 However, especially for hepatocellular carcinoma, the tumor prognosis of LARS1 is rarely reported.…”