Isodeoxyelephantopin induces protective autophagy in lung cancer cells via Nrf2-p62-keap1 feedback loop

Wang, Yang; Zhang, Jing; Huang, Zhi‐Hao; Huang, Xiaohui; Zheng, Wei-Bin; Yin, Xinhua; Li, Yao-Lan; Li, Bin; He, Qing‐Yu

doi:10.1038/cddis.2017.265

Cited by 69 publications

(66 citation statements)

References 63 publications

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“…The crosstalk between autophagy and the Keap1/Nrf2/ARE axis was reported in 2010, and since then great efforts have been made to investigate the underlying molecular mechanisms, particularly in different types of cancers such as hepatocellular carcinoma (16), ovarian cancer (17) and lung cancer (18). A previous study demonstrated that the clinical drug verteporfin induced aggregation of p62 and inhibited autophagy thus suppressing prostate tumorigenesis in a xenograft model (19).…”

Section: Introductionmentioning

confidence: 99%

p62 promotes proliferation, apoptosis‑resistance and invasion of prostate cancer cells through the Keap1/Nrf2/ARE axis

Jiang

Huang

et al. 2020

Oncol Rep

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Prostate cancer poses a public health threat to hundreds of people around the world. p62 has been identified as a tumor suppressor, however, the mechanism by which p62 promotes prostate cancer remains poorly understood. The present study aimed to investigate whether p62 promotes proliferation, apoptosis resistance and invasion of prostate cancer cells via the Kelch-like ECH-associated protein 1/nuclear factor erytheroid-derived 2-like 2/antioxidant response element (Keap1/Nrf2/ARE) axis. Immunohistochemical staining and immunoblotting were performed to determine the protein levels. Rates of proliferation, invasion and apoptosis of prostate cancer cells were assessed using an RTCA system and flow cytometric assays. Levels of reactive oxygen species (ROS) were assessed using Cell ROX Orange reagent and mRNA levels of Nrf2 target genes were detected by qRT-PCR. It was revealed that p62 increased the levels and activities of Nrf2 by suppressing Keap1-mediated proteasomal degradation in prostate cancer cells and tissues, and high levels of p62 promoted growth of prostate cancer through the Keap1/Nrf2/ARE system. Silencing of Nrf2 in DU145 cells overexpressing p62 led to decreases in the rate of cell proliferation and invasion and an increase in the rate of cell apoptosis. p62 activated the Nrf2 pathway, promoted the transcription of Nrf2-mediated target genes and suppressed ROS in prostate cancer. Therefore, p62 promoted the development of prostate cancer by activating the Keap1/Nrf2/ARE pathway and decreasing p62 may provide a new strategy to ameliorate tumor aggressiveness and suppress tumorigenesis to improve clinical outcomes.

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Section: Introductionmentioning

confidence: 99%

p62 promotes proliferation, apoptosis‑resistance and invasion of prostate cancer cells through the Keap1/Nrf2/ARE axis

Jiang

Huang

et al. 2020

Oncol Rep

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“…For example, induction of autophagy is dependent on HO-1 in primary mouse macrophages and hepatocytes (49,50). In lung and colon cancer, HO-1-mediated autophagy sustains cancer cell survival and leads to a more aggressive phenotype (51,52). Conversely, recent studies have shown that HO-1 may also inhibit autophagy to protect renal tubules from cisplatin-mediated injury (31) and modulate hyperthermia-induced antiviral effects in cervical cancer cells (32).…”

Section: Figmentioning

confidence: 99%

Autoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients

Dai

Cai

Wang

et al. 2020

mBio

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Macrophage dysfunction is associated with increased tuberculosis (TB) susceptibility in patients with human immunodeficiency virus (HIV) infection. However, the mechanisms underlying how HIV infection impairs macrophage function are unclear. Here, we found that levels of autoantibodies against red blood cells (RBCs) were significantly elevated in patients with HIV as determined by direct antiglobulin test (DAT). DAT positivity was significantly associated with TB incidence in both univariate and multivariate analyses (odds ratio [OR] = 11.96 [confidence interval {CI}, 4.68 to 30.93] and 12.65 [3.33 to 52.75], respectively). Ex vivo analysis showed that autoantibodies against RBCs enhanced erythrophagocytosis and thus significantly impaired macrophage bactericidal function against intracellular Mycobacterium tuberculosis. Mechanistically, autoantibody-mediated erythrophagocytosis increased heme oxygenase-1 (HO-1) expression, which inhibited M. tuberculosis-induced autophagy in macrophages. Silencing ATG5, a key component for autophagy, completely abrogated the effect of erythrophagocytosis on macrophage bactericidal activity against M. tuberculosis. In conclusion, we have demonstrated that HIV infection increases autoantibody-mediated erythrophagocytosis. This process impairs macrophage bactericidal activity against M. tuberculosis by inhibiting HO-1-associated autophagy. These findings reveal a novel mechanism as to how HIV infection increases TB susceptibility. IMPORTANCE HIV infection significantly increases TB susceptibility due to CD4 T-cell loss and macrophage dysfunction. Although it is relatively clear that CD4 T-cell loss represents a direct effect of HIV infection, the mechanism underlying how HIV infection dampens macrophage function is unknown. Here, we show that HIV infection enhances autoantibody-mediated erythrophagocytosis, which dampens macrophage bactericidal activity against TB by inhibiting HO-1-associated autophagy. Our findings reveal a novel mechanism explaining how HIV infection increases susceptibility to TB. We propose that DAT could be a potential measure to identify HIV patients who are at high TB risk and who would be suitable for anti-TB chemotherapy preventive treatment.

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“…Recent studies have reported the modulation of autophagy pathways by mycotoxin in different cellular models 50 . Currently, several studies have suggested that oxidative stress is linked with autophagy and apoptosis via Nrf2 pathway 28,31,[51][52][53][54][55] . Moreover, Cav-1 has been shown (see figure on previous page) Fig.…”

Section: Discussionmentioning

confidence: 99%

Critical role of caveolin-1 in aflatoxin B1-induced hepatotoxicity via the regulation of oxidation and autophagy

Xu¹,

Shi²,

Lv³

et al. 2020

Cell Death Dis

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Aflatoxin B1 (AFB1) is a potent hepatocarcinogen in humans and exposure to AFB1 is known to cause both acute and chronic hepatocellular injury. As the liver is known to be the main target organ of aflatoxin, it is important to identify the key molecules that participate in AFB1-induced hepatotoxicity and to investigate their underlying mechanisms. In this study, the critical role of caveolin-1 in AFB1-induced hepatic cell apoptosis was examined. We found a decrease in cell viability and an increase in oxidation and apoptosis in human hepatocyte L02 cells after AFB1 exposure. In addition, the intracellular expression of caveolin-1 was increased in response to AFB1 treatment. Downregulation of caveolin-1 significantly alleviated AFB1-induced apoptosis and decreased cell viability, whereas overexpression of caveolin-1 reversed these effects. Further functional analysis showed that caveolin-1 participates in AFB1-induced oxidative stress through its interaction with Nrf2, leading to the downregulation of cellular antioxidant enzymes and the promotion of oxidative stress-induced apoptosis. In addition, caveolin-1 was found to regulate AFB1-induced autophagy. This finding was supported by the effect that caveolin-1 deficiency promoted autophagy after AFB1 treatment, leading to the inhibition of apoptosis, whereas overexpression of caveolin-1 inhibited autophagy and accelerated apoptosis. Interestingly, further investigation showed that caveolin-1 participates in AFB1-induced autophagy by regulating the EGFR/PI3K-AKT/mTOR signaling pathway. Taken together, our data reveal that caveolin-1 plays a crucial role in AFB1-induced hepatic cell apoptosis via the regulation of oxidation and autophagy, which provides a potential target for the development of novel treatments to combat AFB1 hepatotoxicity.

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Isodeoxyelephantopin induces protective autophagy in lung cancer cells via Nrf2-p62-keap1 feedback loop

Cited by 69 publications

References 63 publications

p62 promotes proliferation, apoptosis‑resistance and invasion of prostate cancer cells through the Keap1/Nrf2/ARE axis

p62 promotes proliferation, apoptosis‑resistance and invasion of prostate cancer cells through the Keap1/Nrf2/ARE axis

Autoantibody-Mediated Erythrophagocytosis Increases Tuberculosis Susceptibility in HIV Patients

Critical role of caveolin-1 in aflatoxin B1-induced hepatotoxicity via the regulation of oxidation and autophagy

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