LncRNA XIST/miR-137 axis strengthens chemo-resistance and glycolysis of colorectal cancer cells by hindering transformation from PKM2 to PKM1

Abstract

BACKGROUND: Glycolysis was an essential driver of chemo-resistance in colorectal cancer (CRC), albeit with limited molecular explanations. OBJECTIVE: We strived to elucidate the involvement of lncRNA XIST/miR-137/PKM axis in chemo-tolerance and glycolysis of CRC. METHODS: Altogether 212 pairs of tumor tissues and adjacent normal tissues were collected from CRC patients. Moreover, human CRC epithelial cell lines, including HT29, SW480, SW620 and LoVo, were purchased in advance, and their activity was estimated after transfection of si-XIST or miR-137 mimic. Furthermore, 5-FU/cisplatin-resistance of CRC cells was determined through MTT assay, and glycolytic potential of CRC cells was appraised based on oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). RESULTS: Highly-expressed XIST were predictive of severe symptoms and unfavorable 3-year survival of CRC patients (P< 0.05). Besides, silencing of XIST not only diminished proliferative, migratory and invasive power of CRC cells (P< 0.05), but also enhanced sensitivity of CRC cells responding to 5-FU/cisplatin (P< 0.05). Glycolytic potency of CRC cells was also undermined by si-XIST, with decreased maximal respiration and maximal glycolytic capacity in the si-XIST group as relative to NC group (P< 0.05). Nevertheless, miR-137 mimic attenuated the facilitating effect of pcDNA3.1-XIST on proliferation, migration, invasion, 5-FU/cisplatin-resistance and glycolysis of CRC cells (P< 0.05). Ultimately, ratio of PKM2 mRNA and PKM1 mRNA, despite being up-regulated by pcDNA3.1-XIST, was markedly lowered when miR-137 mimic was co-transfected (P< 0.05). CONCLUSIONS: LncRNA XIST/miR-137 axis reinforced glycolysis and chemo-tolerance of CRC by elevating PKM2/PKM1 ratio, providing an alternative to boost chemo-therapeutic efficacy of CRC patients.

The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer

“…PKM2 is the major isoform in cancer, which can shuttle between the cytoplasm and nucleus, and engages in proliferation, antiapoptosis, metastasis, chemoresistance and other processes in cancer (101)(102)(103). For example, lncRNA XIST/miR-137 axis induces glycolysis and 5-FU/cisplatin resistance in colorectal cancer by elevating the PKM2/PKM1 ratio (104).…”

Exosomal IDH1 increases the resistance of colorectal cancer cells to 5-Fluorouracil

“…PDK2 was highly expressed in 5FU resistant cells, while dichloroacetate or miRNA targeting PDK2 enhanced CRC cell sensitivity to 5FU [33]. LncRNA XIST promoted glycolysis and 5FU chemoresistance in CRC by increasing PKM2 levels [34]. These metabolic enzymes act as direct regulators of glucose metabolism and are responsible for CRC chemoresistance.…”

Long noncoding RNA HULC contributes to paclitaxel resistance in ovarian cancer via miR-137/ITGB8 axis

“…For example, miR-137 targeted dual specificity phosphatase 4 (DUSP4) in breast cancer to inhibit EMT and suppressed doxorubicin resistance [ 35 ]. And miR-137 was suppressed by lncRNA XIST and inhibited 5-FU/cisplatin resistance and glycolysis in colorectal cancer [ 36 ]. In accordance with previous research, the expression level of miR-137 was prominently decreased in PTX-resistant OC tissues and cells.…”