ROS-mediated inactivation of the PI3K/AKT pathway is involved in the antigastric cancer effects of thioredoxin reductase-1 inhibitor chaetocin

Wen, Chuangyu; Wang, Huihui; Wu, Xiaobin; Hé, Lǚ; Zhou, Qian; Wang, Fang; Chen, Siyu; Huang, Likun; Chen, Junxiong; Wang, Huashe; Ye, Wei‐Biao; Li, Wende; Yang, Xiangling; Liu, Huanliang; Peng, Junsheng

doi:10.1038/s41419-019-2035-x

Cited by 81 publications

(63 citation statements)

References 55 publications

(67 reference statements)

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“…This effect was observed in our study, especially in granulocytes and erythrocytes of patients with psoriasis. As a result, these actions weaken the inflammatory response and stimulate the catabolic program of protein and cell growth [ 61 , 62 , 63 ]. Given the significant increase in autophagy and the reduction in the number of erythrocytes and lymphocytes observed in patients with psoriasis [ 64 , 65 ], cell death may be the final result of autophagy in these cases.…”

Section: Discussionmentioning

confidence: 99%

Reduced Proteasome Activity and Enhanced Autophagy in Blood Cells of Psoriatic Patients

Karabowicz

Wroński²,

Ostrowska

et al. 2020

IJMS

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Psoriasis is a skin disease that is accompanied by oxidative stress resulting in modification of cell components, including proteins. Therefore, we investigated the relationship between the intensity of oxidative stress and the expression and activity of the proteasomal system as well as autophagy, responsible for the degradation of oxidatively modified proteins in the blood cells of patients with psoriasis. Our results showed that the caspase-like, trypsin-like, and chymotrypsin-like activity of the 20S proteasome in lymphocytes, erythrocytes, and granulocytes was lower, while the expression of constitutive proteasome and immunoproteasome subunits in lymphocytes was increased cells of psoriatic patients compared to healthy subjects. Conversely, the expression of constitutive subunits in erythrocytes, and both constitutive and immunoproteasomal subunits in granulocytes were reduced. However, a significant increase in the autophagy flux (assessed using LC3BII/LC3BI ratio) independent of the AKT pathway was observed. The levels of 4-HNE, 4-HNE-protein adducts, and proteins carbonyl groups were significantly higher in the blood cells of psoriatic patients. The decreased activity of the 20S proteasome together with the increased autophagy and the significantly increased level of proteins carbonyl groups and 4-HNE-protein adducts indicate a proteostatic imbalance in the blood cells of patients with psoriasis.

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Section: Discussionmentioning

confidence: 99%

Reduced Proteasome Activity and Enhanced Autophagy in Blood Cells of Psoriatic Patients

Karabowicz

Wroński²,

Ostrowska

et al. 2020

IJMS

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“…Reactive oxygen species (ROS) are important signalling molecules in cells, which participate in the transmission of information via multiple signalling pathways [2,3]. Excessive ROS induce tumour cell autophagy and apoptosis by inhibiting PI3K/Akt and other pathways, thereby inhibiting the occurrence and development of tumours [4]. For example, salinomycin promotes autophagy and apoptosis of prostate cancer cells through PI3K/Akt/mTOR and ERK/p38 MAPK pathways by increasing the cellular ROS level [5].…”

Section: Introductionmentioning

confidence: 99%

BDH2 triggers ROS-induced cell death and autophagy by promoting Nrf2 ubiquitination in gastric cancer

Liu

Feng

et al. 2020

J Exp Clin Cancer Res

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Background: 3-Hydroxy butyrate dehydrogenase 2 (BDH2) is a short-chain dehydrogenase/reductase family member that plays a key role in the development and pathogenesis of human cancers. However, the role of BDH2 in gastric cancer (GC) remains largely unclear. Our study aimed to ascertain the regulatory mechanisms of BDH2 in GC, which could be used to develop new therapeutic strategies. Methods: Western blotting, immunohistochemistry, and RT-PCR were used to investigate the expression of BDH2 in GC specimens and cell lines. Its correlation with the clinicopathological characteristics and prognosis of GC patients was analysed. Functional assays, such as CCK-8 and TUNEL assays, transmission electron microscopy, and an in vivo tumour growth assay, were performed to examine the proliferation, apoptosis, and autophagy of GC cells. Related molecular mechanisms were clarified by luciferase reporter, coimmunoprecipitation, and ubiquitination assays. Results: BDH2 was markedly downregulated in GC tissues and cells, and the low expression of BDH2 was associated with poor survival of GC patients. Functionally, BDH2 overexpression significantly induced apoptosis and autophagy in vitro and in vivo. Mechanistically, BDH2 promoted Keap1 interaction with Nrf2 to increase the ubiquitination level of Nrf2. Ubiquitination/degradation of Nrf2 inhibited the activity of ARE to increase accumulation of reactive oxygen species (ROS), thereby inhibiting the phosphorylation levels of Akt Ser473 and mTOR Ser2448. Conclusions: Our study indicates that BDH2 is an important tumour suppressor in GC. BDH2 regulates intracellular ROS levels to mediate the PI3K/Akt/mTOR pathway through Keap1/Nrf2/ARE signalling, thereby inhibiting the growth of GC.

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“…Chaetocin induced apoptosis through the regulation of the mitochondria intrinsic pathway and the inhibition of autophagy on cancerous cells (Jung et al, 2016;Han et al, 2017). Furthermore, chaetocin generates reactive oxygen species which damaged gastric cancer cells via the suppression of the PI3K/AKT tumor progression pathway (Wen et al, 2019). Although exhibiting promising results, some BC cells acquired resistance toward chaetocin and not all tumor-bearing mice survived under the treatment of chaetocin.…”

Section: Discussionmentioning

confidence: 99%

Chaetocin Abrogates the Self-Renewal of Bladder Cancer Stem Cells via the Suppression of the KMT1A–GATA3–STAT3 Circuit

Yang

Wang

Zhang

et al. 2020

Front. Cell Dev. Biol.

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Bladder cancer stem cells (BCSCs) have the abilities of self-renewal, differentiation, and metastasis; confer drug resistance; and exhibit high tumorigenicity. We previously identified that the KMT1A-GATA3-STAT3 axis drives the self-renewal of BCSCs. However, the therapeutic effect of targeting KMT1A in BCSCs remains unknown. In this study, we confirmed that the expression of KMT1A was remarkably higher in BCSCs (3-5-fold) than those in bladder cancer non-stem cells or normal bladder epithelial cells. Among the six KMT1A inhibitors, chaetocin significantly suppressed the cell propagation (inhibition ratio: 65%-88%, IC 50 = 24.4-32.5 nM), induced apoptosis (2-5fold), and caused G1 phase cell cycle arrest (68.9 vs 55.5%) of bladder cancer (BC) cells, without influencing normal bladder epithelial cells. More importantly, chaetocin abrogated the self-renewal of BCSCs (inhibition ratio: 80.1%) via the suppression of the KMT1A-GATA3-STAT3 circuit and other stemness-related pathways. Finally, intravesical instillation of chaetocin remarkably inhibited the growth of xenograft tumors (inhibition ratio: 71-82%) and prolonged the survival of tumor-bearing mice (70 vs 53 days). In sum, chaetocin abrogated the stemness maintenance and tumor growth of BCSCs via the suppression of the KMT1A-GATA3-STAT3 circuit. Chaetocin is an effective inhibitor targeting KMT1A in BCSCs and could be a promising therapeutic strategy for BC.

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ROS-mediated inactivation of the PI3K/AKT pathway is involved in the antigastric cancer effects of thioredoxin reductase-1 inhibitor chaetocin

Cited by 81 publications

References 55 publications

Reduced Proteasome Activity and Enhanced Autophagy in Blood Cells of Psoriatic Patients

Reduced Proteasome Activity and Enhanced Autophagy in Blood Cells of Psoriatic Patients

BDH2 triggers ROS-induced cell death and autophagy by promoting Nrf2 ubiquitination in gastric cancer

Chaetocin Abrogates the Self-Renewal of Bladder Cancer Stem Cells via the Suppression of the KMT1A–GATA3–STAT3 Circuit

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