Molecular alterations contributing to pancreatic cancer chemoresistance

Rajabpour, Azam; Rajaei, Farzad; Teimoori‐Toolabi, Ladan

doi:10.1016/j.pan.2016.12.013

Cited by 36 publications

(24 citation statements)

References 92 publications

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“…The relatively low frequency of complete remissions in neo‐adjuvant trials underscores this as an important clinical issue . Exposure of PDAC cells to components of chemoradiotherapy results in several mechanisms contributing to resistance including activation of survival and anti‐apoptotic pathways . This report uses a novel pharmacologic approach to augment the direct effects of chemoradiotherapy in a series of pre‐clinical PDAC models.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of HSP90 overcomes resistance to chemotherapy and radiotherapy in pancreatic cancer

Nagaraju

Zakka

Landry

et al. 2019

Intl Journal of Cancer

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Resistance of pancreatic ductal adenocarcinoma (PDAC) to radiotherapy and chemotherapy represents a significant clinical issue. Although the mechanisms of resistance are multi-faceted, client proteins of heat shock protein 90 (HSP90) such as hypoxia induced factor-1α (HIF-1α) have a central role in this process. The purpose of this investigation was to evaluate inhibition of HSP90 as a therapeutic strategy for radiosensitization in pancreatic cancer. Ganetespib, a selective inhibitor of HSP90, was evaluated as a radio-sensitizer in setting of PDAC. Inhibition of HSP90 by ganetespib potentiated the ability of radiation therapy to limit cell proliferation and colony formation in vitro. HIF-1α expression was upregulated by irradiation and HIF-1α-overexpressing stable cell lines were resistant to radiation. Inhibition of HSP90 with ganetespib reversed the effects of HIF-1α overexpression, by reducing signaling via proliferative, angiogenic and anti-apoptotic pathways. The potentiation of the antitumor effects of chemoradiotherapy by ganetespib and modulation of key pathways (e.g. HIF-1α, STAT3, and AKT) was confirmed in vivo in nude mice bearing HPAC xenograft tumors. These novel data highlight HIF-1α-mediated mechanisms of HSP90 inhibition that sensitize PDAC cells to chemoradiotherapy. This pathway and its pleiotropic effects warrant further evaluation in concert with conventional therapy in pancreatic cancer clinical trials.

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Section: Discussionmentioning

confidence: 99%

Inhibition of HSP90 overcomes resistance to chemotherapy and radiotherapy in pancreatic cancer

Nagaraju

Zakka

Landry

et al. 2019

Intl Journal of Cancer

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“…Unfortunately, with the emergence of gemcitabine and fluorouracil resistance, the therapeutic efficacy of GEM in pancreatic cancer is declining [7,8]. Recent research on PDA pointed out that the abnormal expression of genes or proteins plays an important role in the occurrence and development of this tumor [9,10]. In general, it is urgent to deepen the understanding of the molecular mechanism of PDA and find new therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

MEX3A knockdown inhibits the development of pancreatic ductal adenocarcinoma

et al. 2020

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Background: Pancreatic ductal adenocarcinoma (PDA) is one of the most serious causes of death in the world due to its high mortality and inefficacy treatments. MEX3A was first identified in nematodes and was associated with tumor formation and may promote cell proliferation and tumor metastasis. So far, nothing is known about the relationship between MEX3A and PDA. Methods:In this study, the expression level of MEX3A in PDA tissues was measured by immunohistochemistry. The qRT-PCR and western blot were used to identify the constructed MEX3A knockdown cell lines, which was further used to construct mouse xenotransplantation models. Cell proliferation, colony formation, cell apoptosis and migration were detected by MTT, colony formation, flow cytometry and Transwell.Results: This study showed that MEX3A expression is significantly upregulated in PDA and associated with tumor grade. Loss-of-function studies showed that downregulation of MEX3A could inhibit cell growth in vitro and in vivo. Moreover, it was demonstrated that knockdown of MEX3A in PDA cells promotes apoptosis by regulating apoptosisrelated factors, and inhibits migration through influencing EMT. At the same time, the regulation of PDA progression by MEX3A involves changes in downstream signaling pathways including Akt, p-Akt, PIK3CA, CDK6 and MAPK9. Conclusions:We proposed that MEX3A is associated with the prognosis and progression of PDA,which can be used as a potential therapeutic target.

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“…Lin et al [14] found that six circulating miRNAs are correlated with overall survival in castration-resistant prostate cancer. Other studies have reported the molecular function and potential clinical utility of miRNAs in PDAC [15,16]. However, the molecular mechanism of miRNAs in pancreatic carcinogenesis remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

miRNA-1290 Promotes Aggressiveness in Pancreatic Ductal Adenocarcinoma by Targeting IKK1

Huang

Zheng

et al. 2018

Cell Physiol Biochem

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Background/Aims: MicroRNAs (miRNAs) are a group of non-coding RNAs that play diverse roles in pancreatic carcinogenesis. In pancreatic ductal adenocarcinoma (PDAC), NF-kB is constitutively activated in most patients and is linked to a mutation in KRAS via IkB kinase complex 1 (IKK1, also known as IKKa). We investigated the link between PDAC aggressiveness and miR-1290. Methods: We used miRCURY^TM LNA Array and in situ hybridization to investigate candidate miRNAs and validated the findings with PCR. The malignant behavior of cell lines was assessed with Cell Counting Kit-8, colony formation, and Transwell assays. A dual-luciferase reporter assay was used to evaluate the interaction between miR-1290 and IKK1. Protein expression was observed by western blotting. Results: In this study, 36 miRNAs were dysregulated in high-grade pancreatic intraepithelial neoplasia (PanIN) and PDAC tissues compared with low-grade PanIN tissues. The area under the curve values of miR-1290 and miR-31-5p were 0.829 and 0.848, respectively (95% confidence interval, 0.722–0.936 and 0.749–0.948, both P < 0.001). There was a significant correlation between miR-1290 and histological differentiation (P = 0.029), pT stage (P = 0.006), and lymph node metastasis (P = 0.001). In addition, the in vitro work showed that miR-1290 promoted PDAC cell proliferation, invasion, and migration. Western blotting and the dual-luciferase reporter assay showed that miR-1290 promoted cancer aggressiveness by directly targeting IKK1. The synergist effect of miR-1290 on the proliferation and metastasis of PDAC cells was attenuated and enhanced by IKK1 overexpression and knockdown, respectively. Consistent with the in vitro results, a subcutaneous tumor mouse model showed that miR-1290 functioned as a potent promoter of PDAC in vivo. Conclusion: MiR-1290 may act as an oncogene by directly targeting the 3’-untranslated region of IKK1, and the miR-1290/IKK1 pathway may prove to be a novel diagnostic and therapeutic target for PDAC.

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Molecular alterations contributing to pancreatic cancer chemoresistance

Cited by 36 publications

References 92 publications

Inhibition of HSP90 overcomes resistance to chemotherapy and radiotherapy in pancreatic cancer

Inhibition of HSP90 overcomes resistance to chemotherapy and radiotherapy in pancreatic cancer

MEX3A knockdown inhibits the development of pancreatic ductal adenocarcinoma

miRNA-1290 Promotes Aggressiveness in Pancreatic Ductal Adenocarcinoma by Targeting IKK1

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