Gemcitabine Resistance is Associated with Epithelial-Mesenchymal Transition and Induction of HIF-1α in Pancreatic Cancer Cells
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Pancreatic cancer is one of the highly aggressive malignant diseases worldwide. To achieve better treatment outcome of pancreatic cancer, in the current study we explore the underlying molecular mechanism of drug resistance in pancreatic cancer cells. We found that resistance to gemcitabine is associated with epithelial-mesenchymal transition (EMT) phenotype in a panel of pancreatic cancer cell lines. Notably, gemcitabine-resistant pancreatic cancer cells acquire EMT phenotype. Moreover, gemcitabine-resistant cells have increased migration and invasion activities. Furthermore, we observed the high expression of HIF-1α in gemcitabine-resistant cells. More importantly, inhibition of HIF-1α in gemcitabine-resistant cells caused partial reversal of EMT phenotype, suggesting that HIF-1α was critically involved in gemcitabine-resistant-mediated EMT. Therefore, targeting HIF-1α could be an effective strategy for the treatment of pancreatic cancer.Cite
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Pancreatic cancer is one of the highly aggressive malignant diseases worldwide. To achieve better treatment outcome of pancreatic cancer, in the current study we explore the underlying molecular mechanism of drug resistance in pancreatic cancer cells. We found that resistance to gemcitabine is associated with epithelial-mesenchymal transition (EMT) phenotype in a panel of pancreatic cancer cell lines. Notably, gemcitabine-resistant pancreatic cancer cells acquire EMT phenotype. Moreover, gemcitabine-resistant cells have increased migration and invasion activities. Furthermore, we observed the high expression of HIF-1α in gemcitabine-resistant cells. More importantly, inhibition of HIF-1α in gemcitabine-resistant cells caused partial reversal of EMT phenotype, suggesting that HIF-1α was critically involved in gemcitabine-resistant-mediated EMT. Therefore, targeting HIF-1α could be an effective strategy for the treatment of pancreatic cancer.
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Pancreatic cancer has extremely poor prognosis. However no satisfactory effective chemotherapy for this cancer has been established. Gemcitabine hydrochloride, a novel anti-tumor agent, had shown the remarkable clinical efficacy for pancreatic cancer. In April 2001, the indication for pancreatic cancer of this agent has been approved in Japan and it is expected to be widely and increasingly introduced for clinical use. This review summarizes the study results of gemcitabine mono-therapy for pancreatic cancer and discusses other possibility of the treatment by Gemcitabine with the reported data about its combination therapy with other anti-cancer drug or radiation.
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Survival rate for pancreatic cancer remains poor and newer treatments are urgently required. Selenium, an essential trace element, offers protection against several cancer types and has not been explored much against pancreatic cancer specifically in combination with known chemotherapeutic agents. The present study was designed to investigate selenium and Gemcitabine at varying doses alone and in combination in established pancreatic cancer cell lines growing in 2D as well as 3D platforms. Comparison of multi-dimensional synergy of combinations' (MuSyc) model and highest single agent (HSA) model provided quantitative insights into how much better the combination performed than either compound tested alone in a 2D versus 3D growth of pancreatic cancer cell lines. The outcomes of the study further showed promise in combining selenium and Gemcitabine when evaluated for apoptosis, proliferation, and ENT1 protein expression, specifically in BxPC-3 pancreatic cancer cells in vitro.
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Pancreatic cancer normally is lethal and difficult to treat.Recently,although chemotherapy drugs such as gemcitabine for the treatment achieved a certain effect, but the survival rate has not improved significantly. Over the past decade, a large number of studies that aimed to implicated in pancreatic tumor gemcitabine metabolism and resistance mechanisms. Recent data show that it is a great value for predicting efficacy in the treatment of pancreatic cancer with gemcitabine by detecting pancreatic cancer -related molecules and genes, especially in the field of individual therapy. This review describes advances in the studies of related molecules and genes affecting the efficacy of gemcitabine for pancreatic cancer.
Key words:
Pancreatic neoplasms; Gemcitabine; Genes; Molecular mechanisms of action
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Pancreatic cancer remains a devastating disease and >96% of patients with pancreatic cancer do not survive for more than 5 years. Gemcitabine (2'-deoxy-2'-difluoro-deoxycytidine: Gemzar) appears to be the only clinically effective drug for pancreatic cancer, but it has little impact on outcome. Proteomic analysis of gemcitabine-sensitive cells (KLM1) and resistant pancreatic cells (KLM1-R) was performed to identify target proteins of the gemcitabine. We found seven proteins, HSP27, peroxiredoxin 2, endoplasmic reticulum protein ERp29 precursor, 6-phosphogluconolactonase, triosphospate isomerase, α enolase, and nucleophosmine that could play a role in determining the sensitivity of pancreatic cancer to gemcitabine. We knocked down HSP27 in KLM1-R and the sensitivity to gemcitabine was restored. In addition, increased HSP27 expression in tumor specimens was related to higher resistibility to gemcitabine in patients of pancreatic cancer. HSP27 may play an important role in the resistibility to gemcitabine, and it could also be a possible biomarker for predicting the response of pancreatic cancer patients to treatment with gemcitabine.
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Owing to the high heterogeneity of pancreatic cancer, patient-derived xenografts (PDX) can compensate for the defects of cell line-derived xenografts (CDX) and also better preserve the heterogeneity and tumor microenvironment of primary tumors. Further, gemcitabine, which is used for the treatment of various cancers, is prone to tumor drug resistance, and this limits its sustained efficacy. Therefore, in this study, our objective was to screen appropriate individual therapeutic drugs for pancreatic cancer. To this end, we established pancreatic cancer PDX models from different patients and screened gemcitabine sensitivity regulatory molecules via high-throughput transcriptome sequencing and bioinformatics analysis. Based on the results obtained, gemcitabine was identified as the most suitable chemotherapeutic drug in a variety of PDX models. Additionally, our results indicated that Lipocalin 2 (LCN 2) may play an important role in the sensitivity of pancreatic cancer to gemcitabine treatment. Thus, the study provides a new potential intervention target for the treatment of pancreatic cancer in clinical practice.
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Objective To investigate the differentially expressed circulating microRNAs of pancreatic cancer,and of the pancreatic cancer with gemcitabine resistance,to find potential biomarkers for noninvasive diagnosis of pancreatic cancer and the prediction of prognosis of gemcitabine.Methods To screen the highly deregulated microRNAs in the plasma samples of pancreatic cancer,and in the plasma samples ofpancreatic cancer patients with gemcitabine resistance using reverse transcription and quantitative PCR.Results Twenty-eight microRNAs expressing differentially with fold-exchange ＞ 2 was screened out comparing pancreatic cancer and healthy controls,and 28 microRNAs was screened out comparing gemcitabine resistant patients and gemcitabine positive patients.Conclusions There is a specific circulating mIcroRNA profile in pancreatic cancer as well as in pancreatic cancer with gemcitabine resistance.These profiles may have potential in noninvasive diagnosis of pancreatic cancer and the prediction of prognosis of gemcitabine.
Key words:
Pancreatic neoplasms ; Plasma; Circulating microRNA ; Gemcitabine; Drug resistance ; MicroRNAs
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Pancreatic cancer is one of the most lethal malignancies accounting for the fourth leading cause of cancer-related deaths in the United States. Among several explored anticancer agents, Gemcitabine, a nucleoside analogue remained a front line chemotherapeutic agent for the treatment of pancreatic cancer. However, gemcitabine exerts a low response rate with limited progression free survival in patients due to cellular resistance of pancreatic tumors to this therapy. Several chemotherapeutic agents have been explored in combination with gemcitabine against pancreatic cancer with overall mixed responses and survival rates. Naturally occurring dietary agents possess promising anticancer properties and have been shown to target various oncogenic signaling pathways in in-vitro and in-vivo pancreatic cancer models.Multiple studies using natural compounds have shown increased therapeutic efficacy of gemcitabine in pancreatic cancer models.This review is focused on recent updates on cellular, preclinical and clinical studies utilizing natural anticancer agents with gemcitabine against pancreatic cancer.
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