Dihydroartemisinin Modulates Apoptosis and Autophagy in Multiple Myeloma through the P38/MAPK and Wnt/<i>β</i>-Catenin Signaling Pathways

Wu, Xi; Liu, Yang; Zhang, Enfan; Chen, Jing; Huang, Xi; Yan, Haimeng; Cao, Wen; Qu, Jianwei; Gu, Huiyao; Xu, Rui‐hua; He, Jingsong; Zhang, Cai

doi:10.1155/2020/6096391

Cited by 33 publications

(29 citation statements)

References 40 publications

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“…We also revealed the mechanism underlying BRG1/Wnt/β-catenin axis in inducing tubular senescence could be related to the inhibition of autophagy. Previous studies have provided evidence that Wnt/β-catenin signalling acts as a crucial negative regulator of autophagy activation [86][87][88]. In line with these findings, we observed that the inhibition of Wnt/β-catenin pathway by ICG-001 reversed BRG1-mediated autophagy suppression, suggesting that BRG1 inhibited autophagy through activating Wnt/β-catenin signalling.…”

Section: Discussionsupporting

confidence: 91%

Brahma-related gene-1 promotes tubular senescence and renal fibrosis through Wnt/β-catenin/autophagy axis

et al. 2021

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Although accelerated cellular senescence is closely related to the progression of chronic kidney disease (CKD) and renal fibrosis, the underlying mechanisms remain largely unknown. Here, we reported that tubular aberrant expression of Brahma-related gene 1 (BRG1), an enzymatic subunit of the SWltch/Sucrose Non-Fermentable complex, is critically involved in tubular senescence and renal fibrosis. BRG1 was significantly upregulated in the kidneys, predominantly in tubular epithelial cells, of both CKD patients and unilateral ureteral obstruction (UUO) mice. In vivo, shRNA-mediated knockdown of BRG1 significantly ameliorated renal fibrosis, improved tubular senescence, and inhibited UUO-induced activation of Wnt/β-catenin pathway. In mouse tubular epithelial cells (mTECs) and primary renal tubular cells, inhibition of BRG1 diminished TGF-β1-induced cellular senescence and fibrotic responses. Correspondingly, ectopic expression of BRG1 in mTECs cells or normal kidneys increased p16INK4a, p19ARF and p21 expression and senescence-associated β-galactosidase activity, indicating accelerated tubular senescence. Additionally, BRG1-mediated pro-fibrotic responses were largely abolished by siRNA-mediated p16INK4a silencing in vitro or continuous senolytic treatment with ABT- 263 in vivo. Moreover, BRG1 activated the Wnt/β-catenin pathway, which further inhibited autophagy. Pharmacologic inhibition of the Wnt/β-catenin pathway (ICG-001) or rapamycin-mediated activation of autophagy effectively blocked BRG1-induced tubular senescence and fibrotic responses, while bafilomycin A1-mediated inhibition of autophagy abolished the effects of ICG-001. Further, BRG1 altered the secretome of senescent tubular cells, which promoted proliferation and activation of fibroblasts. Taken together, our results indicate that BRG1 induces tubular senescence by inhibiting autophagy via the Wnt/β-catenin pathway, which ultimately contributes to the development of renal fibrosis.

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Section: Discussionsupporting

confidence: 91%

Brahma-related gene-1 promotes tubular senescence and renal fibrosis through Wnt/β-catenin/autophagy axis

et al. 2021

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“…Here we also found that overexpression of GADD45B could facilitate phosphorylation of p38 under docetaxel treatment. Considering that p38/MAPK pathway is an important upstream of apoptosis (Fang et al, 2020;Wu et al, 2020), we suggest that GADD45B promotes cell apoptosis through p38/MAPK pathway. It should be noted that overexpression of GADD45B itself did not cause cell apoptosis, even though it could activate p38/MAPK.…”

Section: Discussionmentioning

confidence: 88%

“…Many MAPK pathway–related genes were also up-regulated when GADD45B was overexpressed ( Figure 7F ). Considering that p38/MAPK is an important upstream of apoptosis ( Fang et al, 2020 ; Wu et al, 2020 ), GADD45B might regulate apoptosis by activating p38/MAPK pathway, thus facilitating chemotherapy sensitivity. WB was performed, and it was found that p-p38 was upregulated after docetaxel treatment in DU145 cells.…”

Section: Resultsmentioning

confidence: 99%

GADD45B Is a Potential Diagnostic and Therapeutic Target Gene in Chemotherapy-Resistant Prostate Cancer

Wang

Gao

et al. 2021

Front. Cell Dev. Biol.

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BackgroundChemoresistance is the major cause of death in advanced prostate cancer (PCa), especially in metastatic PCa (mPCa). However, the molecular mechanisms underlying the chemoresistance of PCa remain unclear. Understanding the reason behind the drug resistance would be helpful in developing new treatment approaches.MethodsThe Cancer Genome Atlas, Gene Expression Omnibus datasets, and clinical samples were used to examine the correlation between growth arrest and DNA damage-inducible 45 beta (GADD45B) with clinical characteristics and prognosis. Lentiviral transfection was used to construct GADD45B overexpression cell lines. Hypoxic incubator, low serum medium, or docetaxel was used to build environmental stress model or chemotherapy cell model. The MTS assay and colony formation assay were used to test cell viability. Apoptosis and cell cycle were detected by flow cytometry. The RNA and protein levels of related biomarkers were tested by Western blotting and quantitative polymerase chain reaction. Bioinformatics analysis after RNA sequencing was performed to identify the possible mechanism of how GADD45B regulates chemotherapy resistance.ResultsGADD45B was related to distant metastasis but not to Gleason score, prostate-specific antigen level, T stage, or lymph node metastasis and indicated a good prognosis. The level of GADD45B increased significantly in PCa cells that faced environmental stress. It was found that a high level of GADD45B significantly enhanced the chemosensitivity. Furthermore, high GADD45B promoted cell apoptosis via mitogen-activated protein kinase (MAPK) pathway.ConclusionGADD45B promoted chemosensitivity of prostate cancer through MAPK pathway. GADD45B could serve as a diagnostic biomarker and therapeutic target for mPCa or chemotherapy-resistant patients.

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“…These results indicated that DHA was a safe potential antitumor reagent with low toxicity. Besides the antimalaria activity, DHA has been reported to exhibit significant anticancer activity in a variety of tumors (Dai et al, 2021), including lung cancer (Jiang et al, 2016), ovarian cancer (Li et al, 2018), MM (Wu et al, 2020), and hepatocellular carcinoma (Zou et al, 2019). Previous study demonstrated that inhibition of telomerase activity could reduce the proliferation and migration of esophageal cancer cells (Li et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Human Telomerase Reverse Transcriptase as a Therapeutic Target of Dihydroartemisinin for Esophageal Squamous Cancer

Liu

et al. 2021

Front. Pharmacol.

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Objective: To elucidate the oncogenic role of human telomerase reverse transcriptase (hTERT) in esophageal squamous cancer and unravel the therapeutic role and molecular mechanism of dihydroartemisinin (DHA) by targeting hTERT.Methods: The expression of hTERT in esophageal squamous cancer and the patients prognosis were analyzed by bioinformatic analysis from TCGA database, and further validated with esophageal squamous cancer tissues in our cohort. The Cell Counting Kit-8 (CCK8) and colony formation assay were used to evaluate the proliferation of esophageal squamous cancer cell lines (Eca109, KYSE150, and TE1) after hTERT overexpression or treated with indicated concentrations of DHA. Transwell migration assay and scratch assay were employed to determine the migration abilities of cancer cells. Fluorescence microscopy and flow cytometry were conducted to measure the intracellular reactive oxygen species (ROS) levels in cancer cells after treated with DHA. Moreover, RT-PCR and Western blot were performed to test the alteration of associated genes on mRNA and protein level in DHA treated esophageal squamous cancer cell lines, respectively. Furthermore, tumor-bearing nude mice were employed to evaluate the anticancer effect of DHA in vivo.Results: We found that hTERT was significantly upregulated in esophageal squamous cancer both from TCGA database and our cohort also. Overexpression of hTERT evidently promoted the proliferation and migration of esophageal squamous cancer cells in vitro. Moreover, DHA could significantly inhibit the proliferation and migration of esophageal cancer cell lines Eca109, KYSE150, and TE1 in vitro, and significantly down-regulate the expression of hTERT on both mRNA and protein level in a time- and dose-dependent manner as well. Further studies showed that DHA could induce intracellular ROS production in esophageal cancer cells and down-regulate SP1 expression, a transcription factor that bound to the promoter region of hTERT gene. Moreover, overexpression of SP1 evidently promoted the proliferation and migration of Eca109 and TE1 cells. Intriguingly, rescue experiments showed that inhibiting ROS by NAC alleviated the downregulation of SP1 and hTERT in cells treated with DHA. Furthermore, overexpression of SP1 or hTERT could attenuate the inhibition effect of DHA on the proliferation and migration of Eca109 cells. In tumor-bearing nude mice model, DHA significantly inhibited the growth of esophageal squamous cancer xenografts, and downregulated the expression of SP1 and hTERT protein, while no side effects were observed from heart, kidney, liver, and lung tissues by HE stain.Conclusion: hTERT plays an oncogenic role in esophageal squamous cancer and might be a therapeutic target of DHA through regulating ROS/SP1 pathway.

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Dihydroartemisinin Modulates Apoptosis and Autophagy in Multiple Myeloma through the P38/MAPK and Wnt/β-Catenin Signaling Pathways

Cited by 33 publications

References 40 publications

Brahma-related gene-1 promotes tubular senescence and renal fibrosis through Wnt/β-catenin/autophagy axis

Brahma-related gene-1 promotes tubular senescence and renal fibrosis through Wnt/β-catenin/autophagy axis

GADD45B Is a Potential Diagnostic and Therapeutic Target Gene in Chemotherapy-Resistant Prostate Cancer

Human Telomerase Reverse Transcriptase as a Therapeutic Target of Dihydroartemisinin for Esophageal Squamous Cancer

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