MicroRNA-4290 suppresses PDK1-mediated glycolysis to enhance the sensitivity of gastric cancer cell to cisplatin

Abstract

The development of chemotherapy resistance significantly impairs the efficiency of chemotherapy, but the underlying mechanisms of chemotherapy resistance in gastric cancer (GC) are complicated and still need to be further explored. Here, we aimed to reveal the effects of miR-4290/PDK1 (pyruvate dehydrogenase kinase 1) axis on chemotherapy resistance of GC in vitro. The expression patterns of miR-4290 in GC tissues and cell lines were determined by real-time quantitative PCR. Kaplan-Meier was used to assess the relationship between miR-4290 expression levels and patients' overall survival. CCK-8 and flow cytometry technologies were applied to detect cell proliferation and apoptosis. The luciferase gene reporter assay was used to evaluate the interaction between miR-4290 and PDK1. miR-4290 was lowly expressed in GC tissues and cell lines, which was closely associated with the shorter overall survival of GC patients. miR-4290 mimics significantly inhibited cell proliferation and induced cell apoptosis, as well as induced a significant reduction in the expression of PDK1. Moreover, miR-4290 significantly inhibited glycolysis and decreased the IC50 value to cisplatin in SGC7901 cells, whereas these effects were abolished and cell apoptosis was promoted when PDK1 was overexpressed. In conclusion, this study revealed that miR-4290 suppressed PDK1-mediated glycolysis to enhance the sensitivity of GC cells to cisplatin.

The Implications of PDK1–4 on Tumor Energy Metabolism, Aggressiveness and Therapy Resistance

“…PDK1, a downstream target of hypoxia inducible factor 1 alpha (HIF1a), is upregulated in a number of cancers including ovarian cancer (OCa) (36), gastric cancer (GCa) (37,38), colorectal cancer (CRCa) (39), PCa (40), and acute myeloid leukemia (AML) (41). Involvement of PDK1 has also been implicated in cancer cell epithelial-mesenchymal transition (EMT) and metastasis, for example in metastasis of liver aggressive 4T1 breast cancer (BrCa) cells to the liver, which implies an oncogenic role (12) ( Table 1).…”

“…PDK1-4 have been associated with therapy resistance in several cancers. Qian et al revealed that miR-4290 improved the sensitivity of GCa cells to cisplatin and induced apoptosis by downregulating PDK1 expression (38). Moreover, genetic knockdown of PDK1 abolished hypoxia-induced 5-fluorouracil (5-FU) resistance in GCa cells (74) and sensitized resistant OCa cells to cisplatin-induced cell death and apoptosis (75).…”

<p>MiR-140 Resensitizes Cisplatin-Resistant NSCLC Cells to Cisplatin Treatment Through the SIRT1/ROS/JNK Pathway</p>

“…Recent studies have demonstrated that combination treatment with some miRNAs is able to reduce the chemoresistance of cancers. [35][36][37][38] Among these miRNAs, miR-140 is reported to function as a tumor suppressor. [24][25][26] Furthermore, previous studies have indicated that miR-140 can enhance chemosensitivity of some cancers.…”

Genetic Profiles Affect the Biological Effects of Serine on Gastric Cancer Cells

“…The aberrant activation of PDK1 and its downstream effectors has been reported to involving in pathological phenotypes such as uncontrolled cell proliferation, apoptosis escape, invasion, and metastasis (Qian et al, 2020a), which may explain why HGC-27 cells showed higher metastatic ability in high serine administration in animal experiment. Some researches showed that PDK1 plays a role in chemoresistance in different types of malignancies, and targeting PDK1 could be a selection for promoting chemosensitization (Emmanouilidi and Falasca, 2017;Qian et al, 2020b). Recently, Yuan and colleagues reported that cryptotanshinone, originally a STAT3 inhibitor showed multiple suppressing activity on eight targets with anticancer potential, including MAP2K1, RARalpha, RXRalpha, PDK1, CHK1, AR, Ang-1 R, and Kif11 (Yuan et al, 2014).…”