Overcoming chemoresistance by targeting reprogrammed metabolism: the Achilles' heel of pancreatic ductal adenocarcinoma

Tuerhong, Abudureyimu; Xu, Jin; Shi, Si; Tan, Zhen; Meng, Qingcai; Hua, Jie; Liu, Jiang; Zhang, Bo; Wang, Wei; Yu, Xianjun; Liang, Chen

doi:10.1007/s00018-021-03866-y

Cited by 24 publications

(18 citation statements)

References 191 publications

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“… 30 Furthermore, targeting metabolism reprogramming was an efficient method to overcome the chemoresistance of pancreatic ductal adenocarcinoma. 31 Consequently, targeting glycolysis has been indicated to be an effective means for overcoming chemoresistance, thereby improving cancer therapy. To the best of our knowledge, there is no study related to the effect of CDKN3 on glycolysis.…”

Section: Discussionmentioning

confidence: 99%

CDKN3 Overcomes Bladder Cancer Cisplatin Resistance via LDHA-Dependent Glycolysis Reprogramming

Li¹,

Che²,

Jin³

et al. 2022

OTT

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Background Aerobic glycolysis plays an important role in bladder cancer (BLCA) progression and chemoresistance. Cyclin-dependent kinase inhibitor-3 (CDKN3), a dual-specificity protein tyrosine phosphatase, has aberrant upregulation in multiple cancer types and is associated with tumorigenesis. However, the role of CDKN3 in BLCA progression and glycolysis has not been elucidated. Purpose In this study, we investigated the effect and underlying mechanisms of CDKN3 on bladder cancer chemoresistance. Results This study confirmed that CDKN3 was overexpressed in BLCA tissues and promoted proliferation and migration. Additionally, our results showed a CDKN3-dependent mechanism on chemoresistance; chemoresistance cells were transformed into chemosensitivity cells by CDKN3 knockdown. Additionally, we showed that CDKN3 knockdown decreased glycolysis by inhibiting LDHA expression in BLCA chemoresistance cells. The results also proved that LDHA was an important mediator of CDKN3-regulated BLCA resistance. LDHA overexpression reversed glycolysis inhibition and chemosensitivity induced by CDKN3 downregulation. Conclusion These data collectively identified a vital role of CDKN3 in glycolysis and chemoresistance by regulating LDHA expression in BLCA cells, providing a possible therapeutic strategy for treating BLCA.

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Section: Discussionmentioning

confidence: 99%

CDKN3 Overcomes Bladder Cancer Cisplatin Resistance via LDHA-Dependent Glycolysis Reprogramming

Li¹,

Che²,

Jin³

et al. 2022

OTT

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“…However, due to a series of difficulties such as miRNA carrier, miRNA toxicity evaluation, and effectiveness testing, it cannot be used in clinical practice and treatment at present ( 40 ). And metabolic reprogram is necessary for successful metastasis and effective colonization of distant sites ( 41 ). Though it has been demonstrated that micro RNAs can control tumor growth by regulating glycolysis-related genes ( 42 , 43 ).…”

Section: Discussionmentioning

confidence: 99%

MiR-489-3p Reduced Pancreatic Cancer Proliferation and Metastasis By Targeting PKM2 and LDHA Involving Glycolysis

Zhang¹,

He²,

Shen³

et al. 2021

Front. Oncol.

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IntroductionMalignant proliferation and metastasis are some of the causes of high mortality in pancreatic cancer. MicroRNAs have been a hot spot in cancer research and are involved in tumor formation and metabolic stress responses. However, the biology function and underlying mechanism of miRNA regulating pancreatic cancer progress is remained uncleared.MethodsRNA-seq analysis the glycolysis associated miRNAs and verified miRNA-489-3p was involving in glycolysis. We used RNA in situ hybridization (ISH) and qRT-PCR to analyze the differential expression of miR-489-3p in pancreatic cancer tissues and adjacent tissues and cell lines. Then the function assay of in vivo and in vitro were used to evaluated the role of miR-489-3p in the proliferation, metastasis and glucose metabolism of pancreatic cancer. Furthermore, dual luciferase reporter and rescue experiments were performed to explore the mechanism underlying in the role of miRNA-489-3p.ResultsWe determined that glycolysis associated miRNA miR-489-3p was downregulated in pancreatic cancer tissues and cell lines. The gain and loos of function experiments confirmed that miR-489-3p could inhibit the proliferation, metastasis and glucose metabolism of pancreatic cancer. Further, we found that miR-489-3p could target regulating LDHA and PKM through the luciferase report experiment. Finally, in vivo experiment confirmed that highly expressed miR-489-3p inhibited the growth of pancreatic cancer.ConclusionIn short, this study identified miR-489-3p as a novel therapy target for pancreatic cancer which was involving in the proliferation, metastasis and glycolysis, but its diagnostic value deserves further study.

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“…Despite changes in treatment regimens from monotherapies to multi-agent chemotherapies, the survival rates of PaCa patients remain largely unchanged and success is severely limited due to de novo acquisition or pre-existing resistance. Various intrinsic and extrinsic tumor feature alterations have been proposed contributing to drug resistance, including the microenvironment, altered metabolism, EMT, and the presence of CSCs ( Grasso et al, 2017 ; Swayden et al, 2018 ; Tuerhong et al, 2021 ). The lack of blood vessels and the abundant desmoplasia create a hypoxic and nutrient-scarce environment, forcing PDAC cells to alter their metabolism to sustain proliferation ( Sousa and Kimmelman, 2014 ; Yang et al, 2020 ).…”

Section: Novel Therapeutic Approaches To Target Transcription Factorsmentioning

confidence: 99%

Deregulation of Transcription Factor Networks Driving Cell Plasticity and Metastasis in Pancreatic Cancer

Roey

Brabletz

Stemmler

et al. 2021

Front. Cell Dev. Biol.

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Pancreatic cancer is a very aggressive disease with 5-year survival rates of less than 10%. The constantly increasing incidence and stagnant patient outcomes despite changes in treatment regimens emphasize the requirement of a better understanding of the disease mechanisms. Challenges in treating pancreatic cancer include diagnosis at already progressed disease states due to the lack of early detection methods, rapid acquisition of therapy resistance, and high metastatic competence. Pancreatic ductal adenocarcinoma, the most prevalent type of pancreatic cancer, frequently shows dominant-active mutations in KRAS and TP53 as well as inactivation of genes involved in differentiation and cell-cycle regulation (e.g. SMAD4 and CDKN2A). Besides somatic mutations, deregulated transcription factor activities strongly contribute to disease progression. Specifically, transcriptional regulatory networks essential for proper lineage specification and differentiation during pancreas development are reactivated or become deregulated in the context of cancer and exacerbate progression towards an aggressive phenotype. This review summarizes the recent literature on transcription factor networks and epigenetic gene regulation that play a crucial role during tumorigenesis.

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Overcoming chemoresistance by targeting reprogrammed metabolism: the Achilles' heel of pancreatic ductal adenocarcinoma

Cited by 24 publications

References 191 publications

CDKN3 Overcomes Bladder Cancer Cisplatin Resistance via LDHA-Dependent Glycolysis Reprogramming

CDKN3 Overcomes Bladder Cancer Cisplatin Resistance via LDHA-Dependent Glycolysis Reprogramming

MiR-489-3p Reduced Pancreatic Cancer Proliferation and Metastasis By Targeting PKM2 and LDHA Involving Glycolysis

Deregulation of Transcription Factor Networks Driving Cell Plasticity and Metastasis in Pancreatic Cancer

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