Akt/mTOR signaling pathway is crucial for gemcitabine resistance induced by Annexin II in pancreatic cancer cells

Kagawa, Shingo; Takano, Shigetsugu; Yoshitomi, Hideyuki; Kimura, Fumio; Satoh, Mamoru; Shimizu, Hiroaki; Yoshidome, Hiroyuki; Ohtsuka, Masayuki; Kato, Atsushi; Furukawa, Katsunori; Matsushita, Hiroshi; Nomura, Fumio; Miyazaki, Masaru

doi:10.1016/j.jss.2012.05.065

Cited by 63 publications

(55 citation statements)

References 25 publications

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“…It has been reported earlier that the inhibition of Akt activation enhances the gemcitabine sensitivity in PanC cells (4). We observed significantly higher Akt phosphorylation in GR AsPC-1 cells, and its inhibition by MK-2206 resulted in growth inhibition and induction of cell death.…”

Section: Discussionmentioning

confidence: 86%

“…The other curative treatment of PanC is surgical resection that is possible only in 10–15% of the cases and it only slightly-improves the overall survival rate of 5% after 5 years (3). Although gemcitabine is the first-line chemotherapy for PanC patients, the response rate remains low (4). One of the major mechanisms of drug resistance in these cells is an increased energy-dependent drug efflux, resulting in decreased intracellular drug accumulation (5).…”

Section: Introductionmentioning

confidence: 99%

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Bitter melon juice targets molecular mechanisms underlying gemcitabine resistance in pancreatic cancer cells

Somasagara

Deep

Shrotriya

et al. 2015

International Journal of Oncology

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Pancreatic cancer (PanC) is one of the most lethal malignancies, and resistance towards gemcitabine, the front-line chemotherapy, is the main cause for dismal rate of survival in PanC patients; overcoming this resistance remains a major challenge to treat this deadly malignancy. Whereas several molecular mechanisms are known for gemcitabine resistance in PanC cells, altered metabolism and bioenergetics are not yet studied. Here, we compared metabolic and bioenergetic functions between gemcitabine-resistant (GR) and gemcitabine-sensitive (GS) PanC cells and underlying molecular mechanisms, together with efficacy of a natural agent bitter melon juice (BMJ). GR PanC cells showed distinct morphological features including spindle-shaped morphology and a decrease in E-cadherin expression. GR cells also showed higher ATP production with an increase in oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Molecular studies showed higher expression of glucose transporters (GLUT1 and 4) suggesting an increase in glucose uptake by GR cells. Importantly, GR cells showed a significant increase in Akt and ERK1/2 phosphorylation and their inhibition decreased cell viability, suggesting their role in survival and drug resistance of these cells. Recently, we reported strong efficacy of BMJ against a panel of GS cells in culture and nude mice, which we expanded here and found that BMJ was also effective in decreasing both Akt and ERK1/2 phosphorylation and viability of GR PanC cells. Overall, we have identified novel mechanisms of gemcitabine resistance in PanC cells which are targeted by BMJ. Considering the short survival in PanC patients, our findings could have high translational potential in controlling this deadly malignancy.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Bitter melon juice targets molecular mechanisms underlying gemcitabine resistance in pancreatic cancer cells

Somasagara

Deep

Shrotriya

et al. 2015

International Journal of Oncology

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“…Moreover, Hernandez-Vargas et al34 performed gene expression analysis to shed light on nuclear factor-kappa B pathway activation as a potential mechanism of resistance. Although the AKT/mTOR pathway has been reported to be involved in gemcitabine resistance induced by Annexin II in pancreatic cancer cells,35 the role of PI3K/AKT/mTOR and MAPK signaling pathways and their cross-talk and feedback loops in gemcitabine resistance in breast cancer cells is still unknown. To receive highly effective clinical benefit, dual inhibition of the target plus the subsequent feedback loop is necessary.…”

Section: Discussionmentioning

confidence: 99%

Gemcitabine resistance in breast cancer cells regulated by PI3K/AKT-mediated cellular proliferation exerts negative feedback via the MEK/MAPK and mTOR pathways

Yang¹,

Lin²,

Guo³

et al. 2014

OTT

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Chemoresistance is a major cause of cancer treatment failure and leads to a reduction in the survival rate of cancer patients. Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and mitogen-activated protein kinase (MAPK) pathways are aberrantly activated in many malignant tumors, including breast cancer, which may indicate an association with breast cancer chemoresistance. In this study, we generated a chemoresistant human breast cancer cell line, MDA-MB-231/gemcitabine (simplified hereafter as “231/Gem”), from MDA-MB-231 human breast cancer cells. Flow cytometry studies revealed that with the same treatment concentration of gemcitabine, 231/Gem cells displayed more robust resistance to gemcitabine, which was reflected by fewer apoptotic cells and enhanced percentage of S-phase cells. Through the use of inverted microscopy, Cell Counting Kit-8, and Transwell assays, we found that compared with parental 231 cells, 231/Gem cells displayed more morphologic projections, enhanced cell proliferative ability, and improved cell migration and invasion. Mechanistic studies revealed that the PI3K/AKT/mTOR and mitogen-activated protein kinase kinase (MEK)/MAPK signaling pathways were activated through elevated expression of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-AKT, mTOR, p-mTOR, p-P70S6K, and reduced expression of p-P38 and LC3-II (the marker of autophagy) in 231/Gem in comparison to control cells. However, there was no change in the expression of Cyclin D1 and p-adenosine monophosphate-activated protein kinase (AMPK). In culture, inhibitors of PI3K/AKT and mTOR, but not of MEK/MAPK, could reverse the enhanced proliferative ability of 231/Gem cells. Western blot analysis showed that treatment with a PI3K/AKT inhibitor decreased the expression levels of p-AKT, p-MEK, p-mTOR, and p-P70S6K; however, treatments with either MEK/MAPK or mTOR inhibitor significantly increased p-AKT expression. Thus, our data suggest that gemcitabine resistance in breast cancer cells is mainly mediated by activation of the PI3K/AKT signaling pathway. This occurs through elevated expression of p-AKT protein to promote cell proliferation and is negatively regulated by the MEK/MAPK and mTOR pathways.

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“…Although this method requires time-consuming procedures, we performed this method in the present study. In China, human pancreatic cancer cell line SW1990, which is derived from pancreatic cancer accompanied by metastatic spleen, is commonly used to establish a pancreatic cancer GEM-resistant cell line (10)(11)(12), while MIA PaCa-2 derived from pancreas tissues is used in other countries (13)(14)(15). However, we chose human pancreatic cancer cell line PANC-1, which is derived from pancreatic ductal carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Establishment of human pancreatic cancer gemcitabine-resistant cell line with ribonucleotide reductase overexpression

Wang

Zhang

et al. 2014

Oncology Reports

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Abstract.A gemcitabine (GEM)-resistant human pancreatic cancer cell line (PANC-1RG7) was established in vitro by gradually increasing GEM concentrations and cloning cell cultures to develop a cellular model of acquired drug resistance studies. We found that PANC-1RG7 cells exhibited significantly different morphological characteristics from parental cells. PANC-1RG7 cells grew slowly (p<0.05), yet the cell cycle remained unchanged (p>0.05). PANC-1RG7, with a resistance index to GEM of 39.9, showed cross-resistance characteristics to methotrexate, gefitinib, cisplatin and 5-fluorouracil. The proliferation inhibition of GEM was significantly reduced in vivo (p<0.05). The known resistance-associated genes and proteins we detected remained unchanged, with the exception of cytidine deaminase, multidrug resistance-related protein and breast cancer resistance protein genes, which decreased; by contrast, 5'-nucleotidase, ribonucleotide reductase (RRM) 1 and RRM2 proteins increased (p<0.05). Therefore, a cell line with acquired GEM resistance was established successfully. Resistance was acquired by overexpressing RRM1 and RRM2 proteins. IntroductionPancreatic cancer is a common digestive malignant tumor with low resection rate, high mortality rate and poor prognosis, as the characteristics of this tumor are masked. Pancreatic cancer patients who cannot undergo surgery are subjected to chemotherapy as a fundamental treatment modality; this modality is also a key component of systemic therapy (1).In pancreatic cancer chemotherapy, gemcitabine (GEM) was initially recommended as a first-line drug by the Food and Drug Administration (USA) in 1997. Since then, research on combination chemotherapies, such as cytotoxic drugs [5-fluorouracil (2), cisplatin (3) and capecitabine (4)] and biological agents [erlotinib (5), cetuximab (6) and bevacizumab (7)], as second-line modes of chemotherapy has been extensively conducted. Although GEM is currently the preferred drug for single chemotherapeutic applications in pancreatic cancer, the inherent and acquired resistance of cancer cells to GEM prevents the efficient improvement of the clinical benefit and survival of patients. Furthermore, the efficiency of this treatment is very low (12%) (8); as such, this drawback should be resolved in clinical applications. However, related studies have shown that the prognosis of pancreatic cancer in the past 10 years has remained unchanged.The resistance to GEM is induced by several factors. Although numerous mechanisms have been presented, the main mechanism remains unclear. This resistance is affected by several key molecular factors, including deficiencies in drug uptake, activation of DNA repair pathways, resistance to apoptosis, enhancement of tumor microenvironments, overexpression of signaling proteins, mutations in kinase domains, activation of alternative pathways, mutations of genes and conversion to an epithelial-mesenchymal transition-like phenotype. Hence, GEM-resistance mechanisms involved in pancreatic cancer should be investigated;...

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Akt/mTOR signaling pathway is crucial for gemcitabine resistance induced by Annexin II in pancreatic cancer cells

Cited by 63 publications

References 25 publications

Bitter melon juice targets molecular mechanisms underlying gemcitabine resistance in pancreatic cancer cells

Bitter melon juice targets molecular mechanisms underlying gemcitabine resistance in pancreatic cancer cells

Gemcitabine resistance in breast cancer cells regulated by PI3K/AKT-mediated cellular proliferation exerts negative feedback via the MEK/MAPK and mTOR pathways

Establishment of human pancreatic cancer gemcitabine-resistant cell line with ribonucleotide reductase overexpression

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