Overexpression of miR‐329‐3p sensitizes osteosarcoma cells to cisplatin through suppression of glucose metabolism by targeting LDHA

Abstract

Osteosarcoma (OS) is one of the most frequent malignant bone tumor types. Traditional treatments of OS involve standard chemotherapy or combination with radiation before and after surgery. Cisplatin is one of the most effective chemotherapeutic drugs used for treating osteosarcoma. However, patients with advanced tumor stages develop cisplatin resistance, leading to a major clinical challenge. In this study, we investigated the roles of miR‐329‐3p in cisplatin sensitivity of osteosarcoma cells. We found miR‐329‐3p was significantly downregulated in osteosarcoma tissues compared with normal bone tissues. Overexpression of miR‐329‐3p suppressed osteosarcoma cell proliferation. Moreover, we observed low‐toxic cisplatin treatments suppressed miR‐329‐3p but higher concentrations of cisplatin‐induced miR‐329‐3p expression. In addition, miR‐329‐3p was significantly downregulated in cisplatin‐resistant Saos‐2 cells which displayed elevated glucose metabolism. Overexpression of miR‐329‐3p significantly impaired glucose metabolism of Saos‐2 cells. Bioinformatics analysis and luciferase assay consistently demonstrated the glycolysis enzyme, lactate dehydrogenase‐A (LDHA) was a direct target of miR‐329‐3p in osteosarcoma cells. Rescue experiments revealed restoration of LDHA in miR‐329‐3p‐overexpressed cisplatin‐resistant cells effectively recovered glucose metabolism, resulting in increased cisplatin resistance. This study demonstrates a miR‐329‐3p‐LDHA‐glucose metabolism‐cisplatin resistance axis in osteosarcoma cells, providing a miRNA‐based therapeutic strategy against chemoresistant osteosarcoma.

IGF2BP1-regulated expression of ERRα is involved in metabolic reprogramming of chemotherapy resistant osteosarcoma cells

“…Selectively, shifting glycolysis to mitochondrial oxidation can suppress OS cell growth and metastasis [ 24 ]. Another study revealed that cisplatin-resistant OS cells showed enhanced glucose metabolism [ 25 ]. Additionally, 2-deoxy- d -glucose, a glycolytic inhibitor, could increase the sensitivity of OS cells to paclitaxel [ 26 ].…”

The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer

“…LDHA inhibition can significantly restore the sensitivity of chemotherapy drugs: LDHA knockdown sensitizes oral squamous cell carcinoma cells (122) and breast cancer cells (140) to Taxol and lung cancer cells to low doses of paclitaxel (141) via siRNA/shRNA. MiR-34a re-sensitizes colon cancer cells to 5-FU (142), miR-329-3p sensitizes osteosarcoma cells to cisplatin (143), and miR-7 sensitizes gastric cancer cells to cisplatin (144) all via LDHA inhibition. Recently, increasing studies have begun to explore LDHA inhibitors, which can be divided into three categories, represented by oxamate, 3dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1carboxylic acid(FX11), and N-hydroxyindoles (NHI) (145).…”

The Signature of Glycometabolism-Related Genes in Predicting the Prognosis of Patients with Osteosarcoma

“…Aerobic glycolysis allows the conversion of glucose into pyruvate eventually contributing to the production of lactate. This energy metabolic reprogramming promotes energy generation and thus facilitates OS cells proliferation, invasion, and chemoresistance [19]. Several factors including glycolytic enzymes (e.g., GLUT1), oncogenes (e.g., KRT17), transcription factors (e.g., HIF1α), tumor suppressors (e.g., p53), and related signaling pathways have been reported to regulate the glycometabolism in OS cells and play pivotal roles in overall survival of patients [20][21][22].…”