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- W4246886009 abstract "Abstract Background: Profound chemoresistance is a prominent and intractable problem in pancreatic cancer. Gemcitabine, a first-line chemotherapeutic drug for pancreatic cancer, has provided only minimal benefits for patients; however, the underlying mechanisms remain to be investigated. Enhanced aerobic glycolysis has been suggested to be correlated with the phenotype of drug resistance, while MALAT1 has been indicated to be associated with poor gemcitabine response. However, the implicated regulatory mechanisms still need to be further explored. Methods: The mRNA level of MALAT1, HIF-1α, and glycolytic enzymes were analyzed by qRT-PCR. The protein level of HIF-1α and glycolytic enzymes were detected by western blot analysis. The glucose uptake and lactate level were measured by glucose uptake and lactate production assay, respectively. The cell apoptosis was evaluated by apoptosis analysis using Annexin V/propidium iodide (PI) staining. The sensitivity to gemcitabine was measured by MTT assay. The binding of HIF-1α to the promoter of MALAT1 was tested by ChIP assay. The xenograft model of pancreatic cancer was established to examine the combined effect of MALAT1 knockdown and gemcitabine chemotherapy in vivo. Results: In this study, we showed that low concentrations of gemcitabine promoted the expression of key glycolytic enzymes, such as GLUT1, HK2, and LDHA, as well as glucose uptake and lactate production in pancreatic cancer cells, while inhibition of glycolysis suppressed gemcitabine chemoresistance. In addition, we found that MALAT1 expression was induced by gemcitabine and mediated enhanced glycolysis and chemoresistance. Silencing MALAT1 inhibited the level of gemcitabine-induced HIF-1α expression and reinforced gemcitabine-induced apoptosis in vitro and in vivo. Furthermore, HIF-1α could bind the promoter of MALAT1 transcriptionally and mediate the glycolysis induced by gemcitabine. Conclusions: Our data suggest a critical role of glycolytic metabolism in acquired gemcitabine resistance through the positive feedback loop of MALAT1 and the HIF-1α signaling pathway. Our results will provide a basis for developing potential therapeutic targets to reverse gemcitabine resistance." @default.
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- W4246886009 date "2021-04-12" @default.
- W4246886009 modified "2023-09-29" @default.
- W4246886009 title "The reciprocal loop of MALAT1 and HIF-1α facilitates gemcitabine resistance in pancreatic cancer by enhancing glycolysis" @default.
- W4246886009 doi "https://doi.org/10.21203/rs.3.rs-135235/v2" @default.
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