scholarly journals Ferroptosis: At the Crossroad of Gemcitabine Resistance and Tumorigenesis in Pancreatic Cancer

2021 ◽  
Vol 22 (20) ◽  
pp. 10944
Author(s):  
Jianhui Yang ◽  
Jin Xu ◽  
Bo Zhang ◽  
Zhen Tan ◽  
Qingcai Meng ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Drug Resistance ◽  
Treatment Method ◽  
Resistance Mechanisms ◽  
Ductal Adenocarcinoma ◽  
Intracellular Iron ◽  
Gemcitabine Resistance ◽  
The Past ◽  
New Treatment ◽  
Nonapoptotic Cell Death

The overall five-year survival rate of pancreatic cancer has hardly changed in the past few decades (less than 10%) because of resistance to all known therapies, including chemotherapeutic drugs. In the past few decades, gemcitabine has been at the forefront of treatment for pancreatic ductal adenocarcinoma, but more strategies to combat drug resistance need to be explored. One promising possibility is ferroptosis, a form of a nonapoptotic cell death that depends on intracellular iron and occurs through the accumulation of lipid reactive oxygen species, which are significant in drug resistance. In this article, we reviewed gemcitabine-resistance mechanisms; assessed the relationship among ferroptosis, tumorigenesis and gemcitabine resistance, and explored a new treatment method for pancreatic cancer.

scholarly journals Metabolic plasticity imparts erlotinib-resistance in pancreatic cancer by upregulating glucose-6-phosphate dehydrogenase

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Neha Sharma ◽  
Alok Bhushan ◽  
Jun He ◽  
Gagan Kaushal ◽  
Vikas Bhardwaj
Keyword(s):  
Pancreatic Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Treatment Options ◽  
Pentose Phosphate ◽  
Metabolic Phenotype ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Resistant Cells

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant forms of cancer. Lack of effective treatment options and drug resistance contributes to the low survival among PDAC patients. In this study, we investigated the metabolic alterations in pancreatic cancer cells that do not respond to the EGFR inhibitor erlotinib. We selected erlotinib-resistant pancreatic cancer cells from MiaPaCa2 and AsPC1 cell lines. Metabolic profiling of erlotinib-resistant cells revealed a significant downregulation of glycolytic activity and reduced level of glycolytic metabolites compared to the sensitive cells. The resistant cells displayed elevated expression of the pentose phosphate pathway (PPP) enzymes involved in ROS regulation and nucleotide biosynthesis. The enhanced PPP elevated cellular NADPH/NADP+ ratio and protected the cells from reactive oxygen species (ROS)-induced damage. Inhibition of PPP using 6-aminonicotinamide (6AN) elevated ROS levels, induced G1 cell cycle arrest, and sensitized resistant cells to erlotinib. Genetic studies identified elevated PPP enzyme glucose-6-phosphate dehydrogenase (G6PD) as an important contributor to erlotinib resistance. Mechanistically, our data showed that upregulation of inhibitor of differentiation (ID1) regulates G6PD expression in resistant cells thus contributing to altered metabolic phenotype and reduced response to erlotinib. Together, our results highlight an underlying role of tumor metabolism in PDAC drug response and identify G6PD as a target to overcome drug resistance.

scholarly journals GATA1 Promotes Gemcitabine Resistance in Pancreatic Cancer through Antiapoptotic Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Zhenyu Chang ◽  
Yanan Zhang ◽  
Jie Liu ◽  
Chengjian Guan ◽  
Xinjin Gu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Independent Predictor ◽  
Drug Efficacy ◽  
Ductal Adenocarcinoma ◽  
Cancer Targeting ◽  
First Line ◽  
Effective Strategies ◽  
Gemcitabine Resistance ◽  
Promising Strategy ◽  
First Line Treatment

Gemcitabine-based chemotherapy is the first-line treatment for pancreatic cancer. However, chemoresistance is a major obstacle to drug efficacy, leading to poor prognosis. Little progress has been achieved although multiple mechanisms are investigated. Therefore, effective strategies are urgently needed to overcome drug resistance. Here, we demonstrate that the transcription factor GATA binding protein 1 (GATA1) promotes gemcitabine resistance in pancreatic cancer through antiapoptotic pathway. GATA1 is highly expressed in pancreatic ductal adenocarcinoma (PDAC) tissues, and GATA1 status is an independent predictor of prognosis and response to gemcitabine therapy. Further investigation demonstrates GATA1 is involved in both intrinsic and acquired gemcitabine resistance in PDAC cells. Mechanistically, we find that GATA1 upregulates Bcl-XL expression by binding to its promoter and thus induces gemcitabine resistance through enhancing Bcl-XL mediated antiapoptosis invitroand invivo. Moreover, in PDAC patients, Bcl-XL expression is positively correlated with GATA1 level and predicts clinical outcomes and gemcitabine response. Taken together, our results indicate that GATA1 is a novel marker and potential target for pancreatic cancer. Targeting GATA1 combined with Bcl-XL may be a promising strategy to enhance gemcitabine response.

scholarly journals Effects of Growth Hormone on Pancreatic Cancer Derived Exosomes

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1016-A1017
Author(s):  
Prateek Kulkarni ◽  
Reetobrata Basu ◽  
John J Kopchick
Keyword(s):  
Pancreatic Cancer ◽  
Growth Hormone ◽  
Drug Resistance ◽  
Efflux Pump ◽  
Treatment Options ◽  
The Body ◽  
Ductal Adenocarcinoma ◽  
Gh Treatment ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

Abstract In 2020, the National Cancer Institute (NCI) estimates 57,600 new cases and 47,050 deaths in the US due to pancreatic ductal adenocarcinoma (PDAC). A dismal 10% five-year overall survival rate in PDAC is attributed to late diagnosis, limited treatment options, a remarkably high metastasis rate, and resistance of this cancer to available therapies. Therefore, a better understanding of the mechanisms of how PDAC tumors acquire drug resistance and spread to distal parts of the body are necessary for developing novel therapeutic approaches. Exosomes, microscopic vesicles released from most cells (both tumor and non-tumor) have been recently established to play a significant role in cell to cell communication. Exosomes modulate their target cell responses systematically depending on the nature of exosomal cargoes (nucleic acids, proteins, and lipids). PDAC derived exosomes have been implicated to promote metastasis via forming a pre-metastatic niche of cells as well as enhancing drug resistance. Growth hormone (GH) secreted primarily by the pituitary gland promotes metastasis and drug resistance as shown by plethora of studies. No study has directly assessed the effect of GH on exosomal cargoes in terms of promoting metastases and drug resistance. In this report, we show that GH modulates various pancreatic cancer cell exosomal cargoes which in turn potentially amplifies tumor invasion and metastases. Our data shows that GH treatment on human and mouse PDAC cells increases the exosomal protein levels of TGFβ - a critical inducer of epithelial-to-mesenchymal transition (EMT, a process leading to metastasis). In addition, GH treatment also increases extracellular matrix-degrading enzymes, MMP2 and 9, as well as multi-drug efflux pump ABCC1, ABCB1, and ABCG2 in PDAC cells. These results strongly implicate GH action in driving EMT and chemoresistance via exosomes in pancreatic cancer. Exosomes have a crucial impact especially in the areas of diagnostics and therapeutics. This report is the first to show that GH modulates the effects of exosomes secreted by pancreatic cancer cells. Acknowledgement: This work was supported in part by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, by the AMVETS, and Ohio University’s Student Enhancement Award and Edison Biotechnology Institute.

scholarly journals Cathepsin D Expression and Gemcitabine Resistance in Pancreatic Cancer

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Ujjwal M Mahajan ◽  
Elisabetta Goni ◽  
Enno Langhoff ◽  
Qi Li ◽  
Eithne Costello ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Cathepsin D ◽  
Median Overall Survival ◽  
Validation Cohort ◽  
Multivariable Analysis ◽  
Predictive Marker ◽  
Acid Sphingomyelinase ◽  
Ductal Adenocarcinoma ◽  
Gemcitabine Resistance

Abstract Background Cathepsin-D (CatD), owing to its dual role as a proteolytic enzyme and as a ligand, has been implicated in cancer progression. The role of CatD in pancreatic ductal adenocarcinoma is unknown. Methods CatD expression quantified by immunohistochemistry of tumor-tissue microarrays of 403 resected pancreatic cancer patients from the ESPAC-Tplus trial, a translational study within the ESPAC (European Study Group for Pancreatic Cancer) trials, was dichotomously distributed to low and high H scores (cut off 22.35) for survival and multivariable analysis. The validation cohort (n = 69) was recruited based on the hazard ratio of CatD from ESPAC-Tplus. 5-fluorouracil-, and gemcitabine-resistant pancreatic cancer cell lines were employed for mechanistic experiments. All statistical tests were two-sided. Results Median overall survival was 23.75 months and median overall survival for patients with high CatD expression was 21.09 (95% confidence interval [CI] = 17.31 to 24.80) months vs 27.20 (95% CI = 23.75 to 31.90) months for low CatD expression (χ2LR, 1DF = 4.00; P = .04). Multivariable analysis revealed CatD expression as a predictive marker in gemcitabine-treated (z stat = 2.33; P = .02) but not in 5-fluorouracil-treated (z stat = 0.21; P = .82) patients. An independent validation cohort confirmed CatD as a negative predictive marker for survival (χ2LR, 1DF = 6.80; P = .009) and as an independent predictive marker in gemcitabine-treated patients with a hazard ratio of 3.38 (95% CI = 1.36 to 8.38, P = .008). Overexpression of CatD was associated with a concomitant suppression of the acid sphingomyelinase, and silencing of CatD resulted in upregulation of acid sphingomyelinase with rescue of gemcitabine resistance. Conclusions Adjuvant gemcitabine is less effective in pancreatic ductal adenocarcinoma with high CatD expression, and thus CatD could serve as a marker for biomarker-driven therapy.

scholarly journals ROCK2 Confers Acquired Gemcitabine Resistance in Pancreatic Cancer Cells by Upregulating Transcription Factor ZEB1

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1881 ◽  
Author(s):  
Yang Zhou ◽  
Yunjiang Zhou ◽  
Keke Wang ◽  
Tao Li ◽  
Minda Zhang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Transcriptional Activation ◽  
Coiled Coil ◽  
Ductal Adenocarcinoma ◽  
Dependent Manner ◽  
Promoter Regions ◽  
Gemcitabine Resistance ◽  
Pancreatic Cancer Cells ◽  
Or Gene

Resistance to chemotherapy is a major clinical challenge in the treatment of pancreatic ductal adenocarcinoma (PDAC). Here, we provide evidence that Rho associated coiled-coil containing protein kinase 2 (ROCK2) maintains gemcitabine resistance in gemcitabine resistant pancreatic cancer cells (GR cells). Pharmacological inhibition or gene silencing of ROCK2 markedly sensitized GR cells to gemcitabine by suppressing the expression of zinc-finger-enhancer binding protein 1 (ZEB1). Mechanically, ROCK2-induced sp1 phosphorylation at Thr-453 enhanced the ability of sp1 binding to ZEB1 promoter regions in a p38-dependent manner. Moreover, transcriptional activation of ZEB1 facilitated GR cells to repair gemcitabine-mediated DNA damage via ATM/p-CHK1 signaling pathway. Our findings demonstrate the essential role of ROCK2 in EMT-induced gemcitabine resistance in pancreatic cancer cells and provide strong evidence for the clinical application of fasudil, a ROCK2 inhibitor, in gemcitabine-refractory PDAC.

scholarly journals The Role of miRNAs in the Regulation of Pancreatic Cancer Stem Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Sabrina Bimonte ◽  
Antonio Barbieri ◽  
Maddalena Leongito ◽  
Giuseppe Palma ◽  
Vitale del Vecchio ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Drug Resistance ◽  
Cancer Stem Cells ◽  
Biological Activities ◽  
Biological Properties ◽  
Ductal Adenocarcinoma ◽  
Small Noncoding Rnas ◽  
Pancreatic Cancer Stem Cells

Pancreatic ductal adenocarcinoma is currently one of the deadliest cancers with low overall survival rate. This disease leads to an aggressive local invasion and early metastases and is poorly responsive to treatment with chemotherapy or chemoradiotherapy. Several studies have shown that pancreatic cancer stem cells (PCSCs) play different roles in the regulation of drug resistance and recurrence in pancreatic cancer. MicroRNA (miRNA), a class of newly emerging small noncoding RNAs, is involved in the modulation of several biological activities ranging from invasion to metastases development, as well as drug resistance of pancreatic cancer. In this review, we synthesize the latest findings on the role of miRNAs in regulating different biological properties of pancreatic cancer stem cells.

scholarly journals A pancreas tumor derived organoid study: from drug screen to precision medicine

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jia Yao ◽  
Man Yang ◽  
Lawrence Atteh ◽  
Pinyan Liu ◽  
Yongcui Mao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Tumor ◽  
Ductal Adenocarcinoma ◽  
Drug Screen ◽  
Appreciable Change ◽  
The Past ◽  
Pancreas Tumor ◽  
New Strategy ◽  
Systemic Therapies

AbstractPancreatic ductal adenocarcinoma (PDAC) one of the deadliest malignant tumor. Despite considerable progress in pancreatic cancer treatment in the past 10 years, PDAC mortality has shown no appreciable change, and systemic therapies for PDAC generally lack efficacy. Thus, developing biomarkers for treatment guidance is urgently required. This review focuses on pancreatic tumor organoids (PTOs), which can mimic the characteristics of the original tumor in vitro. As a powerful tool with several applications, PTOs represent a new strategy for targeted therapy in pancreatic cancer and contribute to the advancement of the field of personalized medicine.

scholarly journals Crosstalk between KRAS, SRC and YAP Signaling in Pancreatic Cancer: Interactions Leading to Aggressive Disease and Drug Resistance

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5126
Author(s):  
Enrique Rozengurt ◽  
Guido Eibl
Keyword(s):  
Pancreatic Cancer ◽  
Drug Resistance ◽  
Recent Literature ◽  
Epithelial Mesenchymal Transition ◽  
Ductal Adenocarcinoma ◽  
Current Evidence ◽  
Src Tyrosine Kinase ◽  
Mesenchymal Transition ◽  
New Findings ◽  
Predominant Form

Pancreatic ductal adenocarcinoma (PDAC), the predominant form of pancreatic cancer, remains a devastating disease. The purpose of this review is to highlight recent literature on mechanistic and translational developments that advance our understanding of a complex crosstalk between KRAS, YAP and Src tyrosine kinase family (SFK) in PDAC development and maintenance. We discuss recent studies indicating the importance of RAS dimerization in signal transduction and new findings showing that the potent pro-oncogenic members of the SFK phosphorylate and inhibit RAS function. These surprising findings imply that RAS may not play a crucial role in maintaining certain subtypes of PDAC. In support of this interpretation, current evidence indicates that the survival of the basal-like subtype of PDAC is less dependent on RAS but relies, at least in part, on the activity of YAP/TAZ. Based on current evidence, we propose that SFK propels PDAC cells to a state of high metastasis, epithelial-mesenchymal transition (EMT) and reduced dependence on KRAS signaling, salient features of the aggressive basal-like/squamous subtype of PDAC. Strategies for PDAC treatment should consider the opposite effects of tyrosine phosphorylation on KRAS and SFK/YAP in the design of drug combinations that target these novel crosstalk mechanisms and overcome drug resistance.

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