An Undesired Effect of Chemotherapy

Arora, Sumit; Bhardwaj, Arun; Singh, Seema; Srivastava, Sanjeev K.; McClellan, Steven; Nirodi, Chaitanya S.; Piazza, Gary A.; Grizzle, William E.; Owen, Laurie B.; Singh, Ajay P.

doi:10.1074/jbc.m113.484576

Cited by 147 publications

(90 citation statements)

References 41 publications

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“…Moreover, our data demonstrated that both Akt and ERK played an important role in mediating the effect of PAK4 on subcellular localization of NF-κB/p65 and its transcriptional activity. This is consistent with our recent finding, where we have delineated the cooperative involvement of Akt and ERK pathways in the activation of NF-κB/p65 [40]. In another report, ERK has been identified as a downstream effector pathway mediating PAK4-induced pro-survival effects [41].…”

Section: Discussionsupporting

confidence: 93%

p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-κB pathway

et al. 2014

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Identification of novel molecular targets and understanding the mechanisms underlying the aggressive nature of pancreatic cancer (PC) remain prime focus areas of research. Here, we investigated the expression and pathobiological significance of p21-activated kinase 4 (PAK4), a gene that was earlier shown to be amplified in a sub-set of PC. Our data demonstrate PAK4 overexpression in PC tissues and cell lines with little or no expression in the normal pancreas. PAK4 silencing in two PC cell lines, MiaPaCa and T3M4, by RNA interference causes suppression of growth and clonogenic ability due to decreased cell cycle progression and apoptosis-resistance. PAK4-silenced PC cells exhibit altered expression of proliferation- and survival-associated proteins. Moreover, we observe decreased nuclear accumulation and transcriptional activity of NF-κB in PAK4-silenced PC cells associated with stabilization of its inhibitory protein, IκBα. Transfection of PAK4-silenced PC cells with constitutively-active mutant of IKKβ, an upstream kinase of IκBα, leads to restoration of NF-κB activity and PC cell growth. Furthermore, we show that PAK4-induced NF-κB activity is mediated through activation and concerted action of ERK and Akt kinases. Together, these findings suggest that PAK4 is a regulator of NF-κB pathway in PC cells and can serve as a novel target for therapy.

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Section: Discussionsupporting

confidence: 93%

p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-κB pathway

et al. 2014

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“…More importantly, the recent studies revealed that CXCR4 is correlated with different degree of chemosensitivity of a variety of cancer types, including chemosensitivity of panceatic cancer to GEM[11-15]. Some researches has implicated some miRNAs (like miR-21, miR-200, miR-145) and p85 in the regulation of drug resistance of pancreatic cancer to GEM[1, 8, 16-18].…”

Section: Introductionmentioning

confidence: 99%

CXCR4/Let-7a Axis Regulates Metastasis and Chemoresistance of Pancreatic Cancer Cells Through Targeting HMGA2

Xiao

Wang

2017

Cell Physiol Biochem

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Background/Aims: Pancreatic cancer cells (PCC) is one of the most risky cancers and gemcitabine (GEM) is the standard first-line drug for treating PCC. The PCC will develop drug resistance to GEM after a period of treatment. However, the detailed molecular mechanism of pathogenesis and drug resistance remains unresolved. Methods: we employed qRT-PCR and western blot to examine the expression level of CXCR4, let-7a and HMGA2. In addition, we used MTT assay to detect cell proliferation and transwell assay to measure migration and invasiveness. The expression level of epithelial marker E-cadherin and mesenthymal marker N-cadherin was detected by western blot. The apoptosis was determined using annexin V-FITC/PI apoptosis detection kit by flow cytometry. Results: we first proved that CXCR4 negatively regulated let-7a in PCC. Next, let-7a was confirmed to play crucial role in tumorigenesis, metastasis and drug resistance of pancreatic cancer cells Bxpc-3 and Panc-1 in vitro and in vivo. Finally, we identified HMGA2 as important downsteam target of let-7a in PCC and overexpression of HMGA2 restores cell proliferation, metastasis and chemosensitivity of GEM inhibited by let-7a. Conlusion: Taken together, we show an important signaling pathway involved in pathogenesis and drug resistance of PCC, thereby providing deeper insight into molecular mechanism by which CXCR4/let-7a regulates tumorigenesis and drug resistance of PCC. These findings will help us develop new strategies for diagnosis and treatment of PCC.

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“…Gemcitabine induces intracellular production of reactive oxygen species (ROS) in pancreatic cancer cells, although the contribution of ROS to gemcitabine-induced cancer cell killing is still controversial [38,39]. The study by Donadelli et al showed that gemcitabine-induced ROS plays a role in gemcitabine-mediated cytotoxicity in pancreatic cancer cells, since NAC blunted ROS production and protected cells against gemcitabine toxicity [38].…”

Section: Discussionmentioning

confidence: 99%

“…The study by Donadelli et al showed that gemcitabine-induced ROS plays a role in gemcitabine-mediated cytotoxicity in pancreatic cancer cells, since NAC blunted ROS production and protected cells against gemcitabine toxicity [38]. In contrast, a recent study by Arora et al concluded that gemcitabine-induced ROS production contributed to NFκB-mediated gemcitabine resistance, which was reversed by NAC in MIA PaCa-2 cells in vitro [39]. Although this study was performed in cultured cells, its data support our conclusion that gemcitabine-induced NFκB activation contributes to gemcitabine associated chemo-resistance in vivo (Figs.…”

Section: Discussionmentioning

confidence: 99%

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N-acetyl-l-cysteine sensitizes pancreatic cancers to gemcitabine by targeting the NFκB pathway

Qanungo

Uys

Manevich

et al. 2014

Biomedicine & Pharmacotherapy

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First-line therapy for pancreatic cancer is gemcitabine. Although tumors may initially respond to the gemcitabine treatment, soon tumor resistance develops leading to treatment failure. Previously, we demonstrated in human MIA PaCa-2 pancreatic cancer cells that N-acetyl-l-cysteine (NAC), a glutathione (GSH) precursor, prevents NFκB activation via S-glutathionylation of p65-NFκB, thereby blunting expression of survival genes. In this study, we documented the molecular sites of S-glutathionylation of p65, and we investigated whether NAC can suppress NFκB signaling and augment a therapeutic response to gemcitabine in vivo. Mass spectrometric analysis of S-glutathionylated p65-NFκB protein in vitro showed post-translational modifications of cysteines 38, 105, 120, 160 and 216 following oxidative and nitrosative stress. Circular dichroism revealed that S-glutathionylation of p65-NFκB did not change secondary structure of the protein, but increased tryptophan fluorescence revealed altered tertiary structure. Gemcitabine and NAC individually were not effective in decreasing MIA PaCa-2 tumor growth in vivo. However, combination treatment with NAC and gemcitabine decreased tumor growth by approximately 50%. NAC treatment also markedly enhanced tumor apoptosis in gemcitabine-treated mice. Compared to untreated tumors, gemcitabine treatment alone increased p65-NFκB nuclear translocation (3.7-fold) and DNA binding (2.5-fold), and these effects were blunted by NAC. In addition, NAC plus gemcitabine treatment decreased anti-apoptotic XIAP protein expression compared to gemcitabine alone. None of the treatments, however, affected extent of tumor hypoxia, as assessed by EF5 staining. Together, these results indicate that adjunct therapy with NAC prevents NFκB activation and improves gemcitabine chemotherapeutic efficacy.

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An Undesired Effect of Chemotherapy

Cited by 147 publications

References 41 publications

p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-κB pathway

p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-κB pathway

CXCR4/Let-7a Axis Regulates Metastasis and Chemoresistance of Pancreatic Cancer Cells Through Targeting HMGA2

N-acetyl-l-cysteine sensitizes pancreatic cancers to gemcitabine by targeting the NFκB pathway

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