Reversal of the Apoptotic Resistance of Non-Small-Cell Lung Carcinoma towards TRAIL by Natural Product Toosendanin

Li, Xin; You, Ming; Liu, Yongjian; Ma, Lin; Jin, Peipei; Zhou, Ri; Zhang, Zhao-Xin; Bai, Hua; Ji, Xiaojun; Cheng, Xiaoying; Yin, Fan; Cao, Yan; Wu, Yin

doi:10.1038/srep42748

Cited by 44 publications

(26 citation statements)

References 47 publications

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“…Thus, TAZ is important to keep the stabilization of mitochondrial outer membrane. 19,20 Previous studies have reported that TAZ is overexpressed in multiple cancers. 32,33 Furthermore, research has indicated that TAZ promotes drug resistance in some cancers.…”

Section: Discussionmentioning

confidence: 99%

“…TAZ which is targeted by miR-26b is a mitochondriarelated protein that negatively regulates apoptosis, 19,20 we next studied the role of miR-26b/TAZ axis in cisplatin-induced mitochondrial apoptosis pathway in PC9/ R and A549/R. Results of JC-1 staining showed that overexpression of miR-26b obviously increased the effect of cisplatin on breaking the MMP.…”

Section: Restoration Of Mir-26b Expression Targets Taz To Increase Thmentioning

confidence: 99%

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<p>Restoration of miR-26b expression partially reverses the cisplatin resistance of NSCLC by targeting tafazzin</p>

Zang

Zhao

Gao

et al. 2019

OTT

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Background: Dysregulation of microRNAs has been reported to be responsible for drug resistance of cancers. However, the association between aberrant expression of miR-26b and cisplatin resistance in non-small cell lung cancer (NSCLC) remains unclear. Methods: PC9 and A549 were used to establish the cisplatin resistance models on NSCLC. Expression of miR-26b in cisplatin-resistant PC9 and A549 cells (PC9/R and A549/R) was detected by quantitative real-time PCR assays. Drug sensitivity and mitochondrial apoptosis were detected by Cell Counting Kit-8 assay and flow cytometry assay, respectively. The target relationship between miR-26b and tafazzin (TAZ) was validated by dual-luciferase reporter assay. Results: Obvious downregulation of miR-26b was observed in PC9/R and A549/R cells. Restoration of miR-26b partially reversed the cisplatin resistance of PC9/R and A549/R cells. Expression of TAZ was increased in PC9/R and A549/R cells compared to the parental PC9 and A549 cells. Results of dual-luciferase reporter assays verified that TAZ was targeted by miR-26b. We showed that restoration of miR-26b expression inhibited the TAZ expression and thus expanded the mitochondrial pathway of apoptosis induced by cisplatin in PC9/ R and A549/R cells. Conclusion: Restoration of miR-26b expression partially reverses the cisplatin resistance of NSCLC by targeting TAZ. miR-26b/TAZ axis may represent a potential strategy to reverse the cisplatin in NSCLC.

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Section: Discussionmentioning

confidence: 99%

Section: Restoration Of Mir-26b Expression Targets Taz To Increase Thmentioning

confidence: 99%

<p>Restoration of miR-26b expression partially reverses the cisplatin resistance of NSCLC by targeting tafazzin</p>

Zang

Zhao

Gao

et al. 2019

OTT

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“…More than two-thirds of lung cancer patients are diagnosed at an advance stage (III–IV), and intrinsic and/or acquired resistance to treatment represent major obstacles to the successful treatment of patients with advanced disease (1,2). As compared to other types of lung cancer, non-small cell lung carcinomas (NSCLC) is less prone to undergo spontaneous and treatment-induced apoptosis (3), suggesting that deficiencies in the apoptotic process may be responsible for their and/or acquired resistance to chemotherapy (4).…”

Section: Introductionmentioning

confidence: 99%

PIM Kinases Alter Mitochondrial Dynamics and Chemosensitivity in Lung Cancer

Chauhan

Toth

Jensen

et al. 2019

Preprint

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Resistance to chemotherapy represents a major obstacle to the successful 35 treatment of non-small cell lung cancer (NSCLC). The goal of this study was to determine 36 how PIM kinases impact mitochondrial dynamics, ROS production, and response to 37 chemotherapy in lung cancer. Live cell imaging and microscopy were used to determine 38 the effect of PIM loss or inhibition on mitochondrial phenotype and ROS. Inhibition of PIM 39 kinases caused excessive mitochondrial fission and significant upregulation of 40 mitochondrial superoxide, increasing intercellular ROS. Mechanistically, we define a 41 signaling axis linking PIM1 to Drp1 and mitochondrial fission in lung cancer. PIM inhibition 42 significantly increased the protein levels and mitochondrial localization of Drp1, causing 43 marked fragmentation of mitochondria. An inverse correlation between PIM1 and Drp1 44 was confirmed in NSCLC patient samples. Inhibition of PIM sensitized NSCLC to 45 chemotherapy and produced a synergistic anti-tumor response in vitro and in vivo.46 Immunohistochemistry and transmission electron microscopy verified that PIM inhibitors 47 promote mitochondrial fission and apoptosis in vivo. These data improve our knowledge 48 about how PIM1 regulates mitochondria and provide justification for combining PIM 49 inhibition with chemotherapy in NSCLC. 50 51 52 species 53 54 55Introduction: Lung cancer is the second most commonly diagnosed type of cancer and 56 the leading cause of cancer-related mortality worldwide. More than two-thirds of lung 57 cancer patients are diagnosed at an advance stage (III-IV), and intrinsic and/or acquired 58 resistance to treatment represent major obstacles to the successful treatment of patients 59 with advanced disease (1,2). As compared to other types of lung cancer, non-small cell 60 lung carcinomas (NSCLC) is less prone to undergo spontaneous and treatment-induced 61 apoptosis (3), suggesting that deficiencies in the apoptotic process may be responsible 62 for their and/or acquired resistance to chemotherapy (4). 63Cumulative evidence has demonstrated that an imbalance of mitochondrial fission 64 and fusion is common in cancer (5). Mitochondria exist as a dynamic network that is 65 constantly undergoing fusion (elongation) and fission (fragmentation). Mitochondrial 66 fusion results in a tubular mitochondrial network that serves to counteract metabolic 67 insults, maintain cellular integrity, and provide protection against cell death (6,7). In 68 contrast, mitochondrial fission creates small and fragmented mitochondria, which can 69 have both pro-and anti-tumor effects depending on the cellular context (8). Mitochondrial 70 fission is required for cell division and has been shown to positively regulate cell 71 proliferation in cancer cells (9). However, in response to apoptotic stimuli and cellular 72 stress, too much fission generates excessive reactive oxygen species (ROS) and is a 73 necessary event for the initiation of apoptosis (10). Mitochondrial fusion is associated with 74 chemoresistance in seve...

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“…However, they have been long documented to be toxic drugs [5,6]. Recently, an increasing number of studies have demonstrated the promising anti-tumor efficacy and insecticidal activity of TSN [7][8][9][10][11][12][13]. However, TSN was also reported to induce serious hepatotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Quercetin attenuates toosendanin-induced hepatotoxicity through inducing the Nrf2/GCL/GSH antioxidant signaling pathway

Yao

Huang

et al. 2018

Acta Pharmacol Sin

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Toosendanin (TSN) is the main active compound in Toosendan Fructus and Meliae Cortex, two commonly used traditional Chinese medicines. TSN has been reported to induce hepatotoxicity, but its mechanism remains unclear. In this study, we demonstrated the critical role of nuclear factor erythroid 2-related factor 2 (Nrf2) in protecting against TSN-induced hepatotoxicity in mice and human normal liver L-02 cells. In mice, administration of TSN (10 mg/kg)-induced acute liver injury evidenced by increased serum alanine/aspartate aminotransferase (ALT/AST) and alkaline phosphatase (ALP) activities, and total bilirubin (TBiL) content as well as the histological changes. Furthermore, TSN markedly increased liver reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and decreased liver glutathione (GSH) content and Nrf2 expression. In L-02 cells, TSN (2 μM) time-dependently reduced glutamate-cysteine ligase (GCL) activity and cellular expression of the catalytic/modify subunit of GCL (GCLC/GCLM). Moreover, TSN reduced cellular GSH content and the increased ROS formation, and time-dependently decreased Nrf2 expression and increased the expression of the Nrf2 inhibitor protein kelch-like ECH-associated protein-1 (Keap1). Pre-administration of quercetin (40, 80 mg/kg) effectively inhibited TSN-induced liver oxidative injury and reversed the decreased expression of Nrf2 and GCLC/GCLM in vivo and in vitro. In addition, the quercetin-provided protection against TSN-induced hepatotoxicity was diminished in Nrf2 knock-out mice. In conclusion, TSN decreases cellular GSH content by reducing Nrf2-mediated GCLC/GCLM expression via decreasing Nrf2 expression. Quercetin attenuates TSN-induced hepatotoxicity by inducing the Nrf2/GCL/GSH antioxidant signaling pathway. This study implies that inducing Nrf2 activation may be an effective strategy to prevent TSN-induced hepatotoxicity.

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Reversal of the Apoptotic Resistance of Non-Small-Cell Lung Carcinoma towards TRAIL by Natural Product Toosendanin

Cited by 44 publications

References 47 publications

<p>Restoration of miR-26b expression partially reverses the cisplatin resistance of NSCLC by targeting tafazzin</p>

<p>Restoration of miR-26b expression partially reverses the cisplatin resistance of NSCLC by targeting tafazzin</p>

PIM Kinases Alter Mitochondrial Dynamics and Chemosensitivity in Lung Cancer

Quercetin attenuates toosendanin-induced hepatotoxicity through inducing the Nrf2/GCL/GSH antioxidant signaling pathway

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