Inflammation-mediated SOD-2 upregulation contributes to epithelial-mesenchymal transition and migration of tumor cells in aflatoxin G1-induced lung adenocarcinoma

Li, Yi; Shen, Haitao; Zhao, Ming; Shao, Peilu; Liu, Chunping; Cui, Jinfeng; Wang, Juan; Wang, Can; Guo, Ningfei; Kang, Lifei; Lv, Ping; Xing, Lingxiao; Zhang, Xianghong

doi:10.1038/s41598-017-08537-2

Cited by 42 publications

(30 citation statements)

References 33 publications

(53 reference statements)

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“…Tumor-associated inflammation also participates in the regulation of EMT, which contributes to cancer invasion and metastasis. Yi et al (34) recently reported that SOD may favor inflammation-mediated EMT and migration of tumor cells in AFG1-induced lung adenocarcinoma. We have previously reported that SOD-dependent production of ROS promoted the invasion of pancreatic cancer cells (12).…”

Section: Discussionmentioning

confidence: 99%

Curcumin inhibits superoxide dismutase-induced epithelial-to-mesenchymal transition via the PI3K/Akt/NF-κB pathway in pancreatic cancer cells

Jiang

Xiao

et al. 2018

Int J Oncol

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Curcumin is a natural polyphenol compound derived from turmeric. It possesses multiple pharmacological properties, including antioxidant, anti-inﬂammatory and anti-tumor progression properties. Our recent study demonstrated that superoxide dismutase (SOD)-dependent production of hydrogen peroxide (H2O2) promoted the invasive and migratory activity of pancreatic cancer cells. However, whether curcumin suppresses SOD-induced cancer progression and the related mechanisms remains unclear. Since epithelial‑to-mesenchymal transition (EMT) plays a key role in tumor metastasis, the aim of the present study was to examine whether curcumin intervenes with SOD-induced EMT in pancreatic cancer and the underlying mechanism. The human pancreatic cancer cells BxPC-3 and Panc-1 were exposed to SOD in the presence or absence of curcumin, catalase (CAT, a scavenger of H2O2), or LY 294002 [a phosphoinositide-3 kinase (PI3K) inhibitor]. Intracellular reactive oxygen species (ROS) and H2O2 were evaluated by 2,7-dichlorodihydroﬂuorecein diacetate and H2O2 assay, respectively. The activation of p-Akt and p-nuclear factor (NF)-κB were examined by western blotting. The migratory and invasive abilities of pancreatic cancer cells were tested by the wound healing and Transwell invasion assays. The expression of E-cadherin, N-cadherin and vimentin (EMT-related genes) were measured by reverse transcription-quantitative polymerase chain reaction and western blotting at the mRNA and protein levels, respectively. The findings of the present study demonstrated that curcumin decreased SOD-induced production of ROS and H2O2 in BxPC-3 and Panc-1 cells. Curcumin was able to suppress SOD-induced invasion and migration, and it also regulated the expression of the above‑mentioned EMT-related genes and cell morphology. SOD-induced cell invasion was also inhibited by catalase and LY 294002. Furthermore, the levels of p-Akt and p-NF-κB caused by SOD could be offset by treatment with curcumin and LY 294002. To summarize, these results demonstrated that curcumin was able to prevent SOD-driven H2O2-induced pancreatic cancer metastasis by blocking the PI3K/Akt/NF-κB signaling pathway. The use of curcumin to inhibit the H2O2/Akt/NF-κB axis may be a promising therapeutic approach to the treatment of patients with pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

Curcumin inhibits superoxide dismutase-induced epithelial-to-mesenchymal transition via the PI3K/Akt/NF-κB pathway in pancreatic cancer cells

Jiang

Xiao

et al. 2018

Int J Oncol

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“…However, in various solid tumors, because antioxidant mechanisms are activated at higher levels than in normal cells, tumor cells can be more tolerant to excessive ROS levels than normal cells [77]. NRF2-dependent antioxidant enzymes such as SOD, glutathione peroxidase (GPX), glutathione reductase (GSR), peroxiredoxin (PRX), and thioredoxin reductase (TXNRD) are upregulated in tumor cells, and high expression of these proteins is associated with poor prognosis in tumor patients (Table 1) [78][79][80][81][82][83]. Mitochondrial SOD2 was shown to be highly expressed in ovarian cancer patients and contribute to antitumor therapy resistance [84].…”

Section: Mtor-dependent Antioxidant Mechanism In Solidmentioning

confidence: 99%

mTOR-Mediated Antioxidant Activation in Solid Tumor Radioresistance

Woo

Lee

Jung

et al. 2019

Journal of Oncology

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Radiotherapy is widely used for the treatment of cancer patients, but tumor radioresistance presents serious therapy challenges. Tumor radioresistance is closely related to high levels of mTOR signaling in tumor tissues. Therefore, targeting the mTOR pathway might be a strategy to promote solid tumor sensitivity to ionizing radiation. Radioresistance is associated with enhanced antioxidant mechanisms in cancer cells. Therefore, examination of the relationship between mTOR signaling and antioxidant mechanism-linked radioresistance is required for effective radiotherapy. In particular, the effect of mTOR signaling on antioxidant glutathione induction by the Keap1-NRF2-xCT pathway is described in this review. This review is expected to assist in the identification of therapeutic adjuvants to increase the efficacy of radiotherapy.

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“…The reports related to the relationship between E-cadherin and MSCs are limited to epithelial-mesenchymal transition (EMT) of stem cells. SOD2 is involved in the earlier stage of transition of E-cadherin-to-N-cadherin during EMT of stem cells [33]. Given the requirement of mitochondrial superoxide at the onset of EMT, SOD2 may inhibit EMT in epithelial cells by suppressing mitochondrial ROS.…”

Section: Discussionmentioning

confidence: 99%

“…As a result, SOD2 has roles in protection against cell death, oxidative stress, ionizing radiation, and inflammatory cytokines [31,32]. Mitochondrial SOD2 regulates epithelial-mesenchymal transition and, as a result, the downregulation of E-cadherin, an epithelial marker, in SOD2 knockdown cells is partly inhibited [33]. Additionally, an E-cadherin increase in spheroid formation is proposed to be a key factor that elicits the formation of the spheroid and promotes therapeutic potency of the proliferative and paracrine activity seen in UCB-derived MSCs [29].In this study, we propose that our 3D spheroid MSC culture system, containing aggregated cells tightly adhering to each other, can maintain intracellular functions that are similar to physiological conditions in vivo.…”

mentioning

confidence: 99%

Up-Regulation of Superoxide Dismutase 2 in 3D Spheroid Formation Promotes Therapeutic Potency of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells

et al. 2020

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Umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) are accessible, available in abundance, and have been shown to be a promising source that can regenerate cartilage in patients with osteoarthritis or other orthopedic diseases. Recently, a three-dimensional (3D) cell culture system was developed to mimic the naive tissue microenvironment. However, the efficacy of cells generated from the 3D spheroid culture system has not yet been elucidated. In the present study, we demonstrate the changes in superoxide dismutase 2 (SOD2) gene expression, an indicator of oxidative stress, on 3D spheroid MSCs. Moreover, siRNA transfection and neutralizing antibody investigations were performed to confirm the function of SOD2 and E-cadherin. Overall, we found that SOD2 siRNA transfection in the spheroid form of MSCs increases the expression of apoptotic genes and decreases the clearance of mitochondrial reactive oxygen species (ROS). As a result, we confirm that 3D spheroid formation increases E-cadherin and SOD2 expression, ultimately regulating the phosphoinositide 3-kinase (PI3K/pAkt/pNrf2 and pERK/pNrf2 signaling pathway. Additionally, we show that SOD2 expression on 3D spheroid MSCs affects the regeneration rates of destructive cartilage in an osteoarthritic model. We postulate that the impact of SOD2 expression on 3D spheroid MSCs reduces oxidative stress and apoptosis, and also promotes cartilage regeneration.

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Inflammation-mediated SOD-2 upregulation contributes to epithelial-mesenchymal transition and migration of tumor cells in aflatoxin G1-induced lung adenocarcinoma

Cited by 42 publications

References 33 publications

Curcumin inhibits superoxide dismutase-induced epithelial-to-mesenchymal transition via the PI3K/Akt/NF-κB pathway in pancreatic cancer cells

Curcumin inhibits superoxide dismutase-induced epithelial-to-mesenchymal transition via the PI3K/Akt/NF-κB pathway in pancreatic cancer cells

mTOR-Mediated Antioxidant Activation in Solid Tumor Radioresistance

Up-Regulation of Superoxide Dismutase 2 in 3D Spheroid Formation Promotes Therapeutic Potency of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells

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