Bmi1 inhibition enhances the sensitivity of pancreatic cancer cells to gemcitabine

Cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT)‐type cells are considered as underlying causes of chemoresistance, tumour recurrence and metastasis in pancreatic cancer. We aimed to describe the mechanisms – particularly glycolysis – involved in the regulation of the CSC and EMT phenotypes. We used a gemcitabine‐resistant (GR) Patu8988 cell line, which exhibited clear CSC and EMT phenotypes and showed reliance on glycolysis. Inhibition of glycolysis using 2‐deoxy‐D‐glucose (2‐DG) significantly enhanced the cytotoxicity of gemcitabine and inhibited the CSC and EMT phenotypes in GR cells both in vitro and in vivo. Intriguingly, the use of the reactive oxygen species (ROS) scavenger N‐acetylcysteine (NAC) restored the CSC and EMT phenotypes. H2O2 produced changes similar to those of 2‐DG, indicating that ROS were involved in the acquired cancer stemness and EMT phenotypes of GR cells. Moreover, doublecortin‐like kinase 1 (DCLK1), a pancreatic CSC marker, was highly expressed and regulated the stemness and EMT phenotypes in GR cell. Both 2‐DG and H2O2 treatment suppressed DCLK1 expression, which was also rescued by NAC. Together, these findings revealed that glycolysis promotes the expression of DCLK1 and maintains the CSC and EMT phenotypes via maintenance of low ROS levels in chemoresistant GR cells. The glycolysis‐ROS‐DCLK1 pathway may be potential targets for reversing the malignant behaviour of pancreatic cancer.

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“…This was conducted as described previously . Cells (6000/well) were seeded in 96‐well plates overnight.…”

Section: Methodsmentioning

confidence: 99%

Up‐regulation of glycolysis promotes the stemness and EMT phenotypes in gemcitabine‐resistant pancreatic cancer cells

Zhao

Duan

Zhang

et al. 2017

J Cellular Molecular Medi

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134

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“…Evidence from other studies also demonstrate the effectiveness of specific induction of ROS as it relates to gemcitabine efficacy; Donadelli et al showed that trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor enhanced gemcitabine-mediated cytotoxicity in vitro and blocked the growth of T3M4 human pancreatic cancer cells in vivo [152] Additionally, genetic inhibition of Bmi1 was shown to augment gemcitabine sensitivity in pancreatic cancer cells [153], and in both of these cases, the enhanced effectiveness of gemcitabine was dependent on increased ROS production.…”

Section: Targeting Ros In Pda Development and Progressionmentioning

confidence: 99%

Targeting reactive oxygen species in development and progression of pancreatic cancer

Durand

Störz

2016

Expert Review of Anticancer Therapy

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Introduction Pancreatic ductal adenocarcinoma (PDA) is characterized by expression of oncogenic KRas which drives all aspects of tumorigenesis. Oncogenic KRas induces the formation of reactive oxygen species (ROS) which have been implicated in initiation and progression of PDA. To facilitate tumor promoting levels and to avoid oncogene-induced senescence or cytotoxicity, ROS homeostasis in PDA cells is balanced by additional up-regulation of antioxidant systems. Areas Covered We examine the sources of ROS in PDA, the mechanisms by which ROS homeostasis is maintained, and the biological consequences of ROS in PDA. Additionally, we discuss the potential mechanisms for targeting ROS homoeostasis as a point of therapeutic intervention. An extensive review of the relevant literature as it relates to the topic was conducted using PubMed. Expert Commentary Even though oncogenic mutations in the KRAS gene have been detected in over 95% of human pancreatic adenocarcinoma, targeting its gene product, KRas, has been difficult. The dependency of PDA cells on balancing ROS homeostasis could be an angle for new prevention or treatment strategies. These include use of antioxidants to prevent formation or progression of precancerous lesions, or methods to increase ROS in tumor cells to toxic levels.

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“…BMI-1 is an oncogene and over expression is associated with poor prognosis 18,28 . BMI-1 promotes PDAC invasion and metastasis and inhibition of BMI-1 enhances gemcitabine sensitivity 29,30 .…”

Section: Discussionmentioning

confidence: 99%

Functional significance and therapeutic potential of miR-15a mimic in pancreatic ductal adenocarcinoma

Guo

Fesler

Huang

et al. 2019

Preprint

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Treatment of pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge.There is an urgent need to develop novel strategies to enhance survival and improve patient prognosis. microRNAs (miRNAs) play critical roles as oncogenes or tumor suppressors in the regulation of cancer development and progression. In this study, we demonstrate that low expression of miR-15a is associated with poor prognosis of PDAC patients. miR-15a expression is reduced in PDAC while closely related miR-16 expression remains relatively unchanged. miR-15a suppresses several important targets such as Wee1, Chk1, Yap-1, and BMI-1 causing cell cycle arrest and inhibiting cell proliferation. Ectopic expression of miR-15a sensitizes PDAC cells to gemcitabine reducing the IC 50 over 6.5-fold. To investigate the therapeutic potential of miR-15a, we used a modified miR-15a (5-FU-miR-15a) with uracil (U) residues in the guide strand replaced with 5-fluorouracil (5-FU). We demonstrated enhanced inhibition of PDAC cell proliferation by 5-FU-miR-15a compared to native miR-15a. In vivo we showed the therapeutic power of 5-FU-miR-15a alone or in combination with gemcitabine with near complete elimination of PDAC lung metastatic tumor growth. These results support the future development of 5-FU-miR-15a as a novel therapeutic agent as well as a prognostic biomarker in the clinical management of PDAC. Introduction:

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Bmi1 inhibition enhances the sensitivity of pancreatic cancer cells to gemcitabine

Cited by 18 publications

References 36 publications

Up‐regulation of glycolysis promotes the stemness and EMT phenotypes in gemcitabine‐resistant pancreatic cancer cells

Up‐regulation of glycolysis promotes the stemness and EMT phenotypes in gemcitabine‐resistant pancreatic cancer cells

Targeting reactive oxygen species in development and progression of pancreatic cancer

Functional significance and therapeutic potential of miR-15a mimic in pancreatic ductal adenocarcinoma

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