Inhibition of lactate dehydrogenase A by microRNA-34a resensitizes colon cancer cells to 5-fluorouracil

Abstract

5-Fluorouracil (5-FU) chemotherapy is widely used in the treatment of advanced colon cancer. However, the development of resistance to 5-FU is a significant obstacle to successful treatment. MicroRNA-34a (miR-34a) has been reported to be downregulated in a number of tumor types and has also been shown to act as a tumor suppressor. However, the mechanisms underlying the biological effects of miR-34a in chemoresistance remain unclear. The present study showed that the expression of miR-34a is downregulated in 5-FU-resistant colon cancer cells. In addition, 5-FU-resistant colon cancer cells exhibited upregulation of lactate dehydrogenase A (LDHA) expression and activity compared with parental cells. Furthermore, LDHA was shown to be a direct target of miR-34a. Overexpression of miR-34a reduced the expression of LDHA, probably through binding to the 3' untranslated region, leading to the re-sensitization of 5-FU-resistant cancer cells to 5-FU. Additionally, overexpression of LDHA rendered colon cancer cells resistant to 5-FU, suggesting that the miR-34a-induced sensitization to 5-FU is mediated through the inhibition of LDHA. In conclusion, the current study showed that miR-34a is involved in sensitivity to 5-FU in part through its effects on LDHA expression. This indicates that miR-34a‑mediated inhibition of glucose metabolism may be a therapeutic target in patients with chemoresistant colon cancer.

Increased Lactate in Gastric Cancer Tumor-Infiltrating Lymphocytes Is Related to Impaired T Cell Function Due to miR-34a Deregulated Lactate Dehydrogenase A

“…We found that miR-34a expression was decreased in T cells, which contributed to the increase in LDHA in human GC TILs. Several studies have revealed that LDHA is one of the target genes of miR-34a in different cancer tissues including breast cancer and colorectal cancer (CRC) [15,16,21]. Our results also indicated a similar outcome in that miR-34a downregulated LDHA expression in T cells.…”

“…Lactic acid has the formula CH 3 CH(OH)CO 2 H. The anion lactate CH 3 CH(OH)CO 2 − is the predominant moiety present in the human body, as the pKa of the lactate/lactic acid pair is 3.8 [15,17,18]. Pyruvate is the final product of glycolysis, yielding two moles of ATP for each molecule of glucose in the process [17].…”

“…To investigate the mechanism of increased LDHA in T cells, we detected the expression of miR-34a, which is reported to downregulate LDHA expression by targeting its 3' UTR [15,16]. miR-34a was significantly decreased in GC TILs and peripheral T cells compared to those from healthy controls (Fig.…”

The Network of Non-coding RNAs in Cancer Drug Resistance

“…It is down-modulated in colorectal cancer (CRC) (100). In 5-Fluorouracil (5-FU)-resistant colon cancer cells ectopic expression of miR-34a inhibited cell growth and attenuated the resistance to 5-FU through down-regulation of SIRT1 and E2F3 (101), inhibition of LDHA (102) and of c-Kit, thus reducing stem cell factor (SCF)-induced migration/invasion (103). Yang et al demonstrated that miR-34 targets BCL2 and sensitizes HCC cells to sorafenib (104).…”

“…Like let-7c, also present in this subnetwork, let-7b resulted important for development of 5-FU chemoresistance in RCC (221). miR-34a also plays a role in resistance to 5-FU and to vemurafenib (102, 103, 388). The expression profile of lncRNAs was investigated in 5-FU-resistant colon cancer cell lines and snaR was confirmed to be downregulated (389); this loss increases cell viability after 5-FU treatment, suggesting that this lncRNA has a potential role as a negative regulator in drug response (390).…”