Gefitinib induces lung cancer cell autophagy and apoptosis via blockade of the PI3K/AKT/mTOR pathway

Zhao, Zhongquan; Yu, Zhenhua; Li, Jie; Ouyang, Xin

doi:10.3892/ol.2016.4606

Cited by 71 publications

(50 citation statements)

References 38 publications

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“…Gefitinib induced apoptosis of NSCLC cells through direct inhibition of pro-survival p-EGFR, p-Akt, and p-Erk1/2 (Mukohara et al , 2005; Zhao et al , 2016b), which was also manifested in our study by gefitinib treatment in A549. On the other hand, LMB, as a specific CRM1 inhibitor of the nuclear export signal (NES)-dependent transport (Lu et al , 2015), was found to significantly upregulate the expressions of p-Erk1/2 and p-Akt in A549 in the present study.…”

Section: Discussionsupporting

confidence: 77%

Leptomycin B reduces primary and acquired resistance of gefitinib in lung cancer cells

Liu

Gao

2017

Toxicology and Applied Pharmacology

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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib has demonstrated dramatic clinical efficacy in non-small cell lung cancer (NSCLC) patients. However, its therapeutic efficacy is ultimately limited by the development of acquired drug resistance. The aim of this study was to explore the potential utility of chromosome region maintenance 1 (CRM1) inhibitor leptomycin B (LMB) in combination with gefitinib to overcome primary and acquired gefitinib resistance in NSCLC cells. The combinative effects of gefitinib and LMB were evaluated by MTT and its underlining mechanism was assessed by flow cytometry and Western blot. LMB displayed a synergistic effect on gefitinib- induced cytotoxicity in A549 (IC50: 25.0±2.1 μM of gefitinib+LMB vs. 32.0±2.5 μM of gefitinib alone, p<0.05). Gefitinib+LMB caused a significantly different cell cycle distribution and signaling pathways involving in EGFR/survivin/p21 compared with gefitinib. A549 cells then were treated with progressively increasing concentrations of gefitinib (A549GR) or in combination with LMB (A549GLR) over 10 months to generate gefitinib resistance. IC50 of gefitinib in A549GLR (37.0±2.8 μM) was significantly lower than that in A549GR (53.0±3.0 μM, p<0.05), which indicates that LMB could reverse gefitinib-induced resistance in A549. Further mechanism investigation revealed that the expression patterns of EGFR pathway and epithelial- mesenchymal transition (EMT) markers in A549, A549GR, and A549GLR were significantly different. In conclusion, LMB at a very low concentration combined with gefitinib showed synergistic therapeutic effects and ameliorated the development of gefitinib- induced resistance in lung cancer cells.

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Section: Discussionsupporting

confidence: 77%

Leptomycin B reduces primary and acquired resistance of gefitinib in lung cancer cells

Liu

Gao

2017

Toxicology and Applied Pharmacology

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“…ERS shares a correlation with the PI3K/Akt/mTOR signaling pathway. Our experimental data revealed that increases in ERS are followed by decreases in PI3K/AKT/mTOR signaling, as well as reductions in chemoresistance; when the PI3K/AKT/mTOR signaling pathway is blocked, autophagy and apoptosis factors are increased, chemotherapy resistance is weakened, and the tumor shrinks [27, 59], which has an important function in autophagy and apoptosis regulation [2, 60, 61]. It has been reported that blocking the PI3K/AKT/mTOR cascade promotes autophagy [62] that inhibiting PI3K/Akt/mTOR signaling promotes cell apoptosis in LC [28], which is consistent with our results.…”

Section: Discussionmentioning

confidence: 99%

“…As one of the most common malignant tumors worldwide, the leading risk factors involved with the occurrence of LC include both smoking as well as exposure and environmental factors [2]. The disease manifests itself with severe impairment of both patient health and quality of life [3].…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Promotes Autophagy and Apoptosis and Reduces Chemotherapy Resistance in Mutant p53 Lung Cancer Cells

Gan

Zhou

Zhong

et al. 2017

Cell Physiol Biochem

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Background/Aims: Lung cancer (LC) continues to be one of the most prevalent cancers around the world. During this study we aimed to investigate the involvement of endoplasmic reticulum stress (ERS) in autophagy, apoptosis, and chemotherapy resistance of mutant p53 LC cells. Methods: Immunohistochemistry was employed to help determine the p53 mutation status of cancer cells from 92 primary LC patients, who were subsequently assigned to either the mutant p53 (n = 39) or wild-type p53 group (n = 53). Results: Mutant p53 cells exhibited increased expression of the C/EBP homologous protein (CHOP), glucose-regulated protein 78 (GRP78), and inositol-requiring enzyme-1α (IRE1α). The Mutant p53 cells were also found to be sensitive to chemotherapy and displayed decreased expression of PI3K, Akt, and mTOR. The mutant p53 cell lines were treated with tunicamycin to induce ERS and rapamycin in order to inhibit mTOR. Both agents increased the expression of CHOP, GRP78, IRE1α, LC3-II/LC3-I, Atg5, Atg7, caspase-3, caspase-12, cleaved caspase-3, cleaved caspase-12, as well as decreases in cell proliferation as well as the expression levels of PI3K, Akt, and mTOR. Enhanced levels of cell apoptosis and reduced chemotherapy resistance were also detected. Conclusion: The findings of our study suggest that ERS promotes autophagy and apoptosis, while acting to reduce chemotherapy resistance in mutant p53 LC cells by downregulating the PI3K/Akt/mTOR signaling pathway.

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“…8). In contrast, several studies have shown that blocking the Akt/mTOR pathway suppresses proliferation and promotes apoptosis in many kinds of tumors [38,39]. As mTOR controls cap-dependent translation [36], we hypothesize a possible mechanism whereby the activation of mTOR increases protein synthesis, which may then consume a lot of energy (ATP) and generate high levels of ROS.…”

Section: Discussionmentioning

confidence: 81%

The Transient Receptor Potential Channel, Vanilloid 5, Induces Chondrocyte Apoptosis via Ca2+ CaMKII–Dependent MAPK and Akt/ mTOR Pathways in a Rat Osteoarthritis Model

Wei

Jin

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Chondrocyte apoptosis is a central pathological feature of cartilage in osteoarthritis (OA). Accumulating evidence suggests that calcium ions (Ca²⁺) are an important regulator of apoptosis. Previously, we reported that the transient receptor potential channel vanilloid (TRPV5) is upregulated in monoiodoacetic acid (MIA)-induced OA articular cartilage. Methods: The protein levels of TRPV5, phosphorylated Ca²⁺/calmodulin-dependent kinase II (p-CaMKII), and total CaMKII were detected in vivo using western blotting techniques. Primary chondrocytes were isolated and cultured in vitro. Then, p-CAMKII was immunolocalized by immunofluorescence in chondrocytes. Fluo-4AM staining was used to assess intracellular Ca²⁺. Annexin V-fluorescein isothiocyanate / propidium iodide flow cytometric analysis was performed to determine chondrocyte apoptosis. Western blotting techniques were used to measure the expression of apoptosis-related proteins. Results: We found that ruthenium red (aTRPV5inhibitor)or(1-[N,O-bis-(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperaze (KN-62) (an inhibitor of Ca^2+/calmodulin-dependent kinase II (CaMKII) phosphorylation) can relieve or even reverse OA in vivo. We found that TRPV5 has a specific role in mediating extracellular Ca²⁺ influx leading to chondrocyte apoptosis in vitro. The apoptotic effect in chondrocytes was inhibited by KN-62. We found that activated p-CaMKII could elicit the phosphorylation of extracellular signal-regulated protein kinase 1/2, c-Jun N-terminal kinase, and p38, three important regulators of the mitogen-activated protein kinase (MAPK) cascade. Moreover, we also showed that activated p-CaMKII could elicit the phosphorylation of protein kinase B (Akt) and two important downstream regulators of mammalian target of rapamycin (mTOR): 4E-binding protein, and S61 kinase. Conclusion: Our results demonstrate that upregulated TRPV5 may be an important initiating factor that activates CaMKII phosphorylation via the mediation of Ca²⁺ influx. In turn, activated p-CaMKII plays a critical role in chondrocyte apoptosis via MAPK and Akt/mTOR pathways.

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Gefitinib induces lung cancer cell autophagy and apoptosis via blockade of the PI3K/AKT/mTOR pathway

Cited by 71 publications

References 38 publications

Leptomycin B reduces primary and acquired resistance of gefitinib in lung cancer cells

Leptomycin B reduces primary and acquired resistance of gefitinib in lung cancer cells

Endoplasmic Reticulum Stress Promotes Autophagy and Apoptosis and Reduces Chemotherapy Resistance in Mutant p53 Lung Cancer Cells

The Transient Receptor Potential Channel, Vanilloid 5, Induces Chondrocyte Apoptosis via Ca2+ CaMKII–Dependent MAPK and Akt/ mTOR Pathways in a Rat Osteoarthritis Model

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