Effects and Mechanisms of Saikosaponin D Improving the Sensitivity of Human Gastric Cancer Cells to Cisplatin

Hu, Jianran; Li, Ping; Shi, Bibo; Tie, Jun

doi:10.1021/acsomega.1c01795

Cited by 18 publications

(9 citation statements)

References 45 publications

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“…The mechanism of how KIAA1429 was up-regulated in cisplatin resistant GC cells remains unknown. p65, an important transcriptional factor, has been proven to be involved in cisplatin resistance in multiple cancer types, including GC [ 36 , 37 ]. In addition, p65 bound the promoter area of METTL14, and regulated its expression in pancreatic cancer cells [ 38 ].…”

Section: Resultsmentioning

confidence: 99%

“…Transcriptional factor p65 was found to be involved in cisplatin resistance in several cancers. In addition, p65 regulated the gemcitabine resistance in pancreatic cancer via promoting the expression of METTL14 [ 36 , 37 , 38 ]. The activity of p65 relies on its phosphorylation, and p65 phosphorylation was found to be increased in our cisplatin resistant GC cells.…”

Section: Discussionmentioning

confidence: 99%

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m6A Methyltransferase KIAA1429 Regulates the Cisplatin Sensitivity of Gastric Cancer Cells via Stabilizing FOXM1 mRNA

Zhu

Zhou

Chen

et al. 2022

Cancers

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Although cisplatin is frequently used to treat gastric cancer, the resistance is the main obstacle for effective treatment. mRNA modification, N6-methyladenosine (m6A), is involved in the tumorigenesis of many types of cancer. As one of the largest m6A methyltransferase complex components, KIAA1429 bridges the catalytic m6A methyltransferase components, such as METTL3. In gastric cancer, KIAA1429 was reported to promote cell proliferation. However, whether KIAA1429 is involved in the resistance of gastric cancer to cisplatin remains unclear. Here, we generated cisplatin resistant gastric cancer cell lines, and compared the m6A content between resistant cells and wild type cells. The m6A content as well as KIAA1429 expression are higher in resistant cells. Interestingly, the expression of KIAA1429 was significantly increased after cisplatin treatment. We then used shRNA to knockdown KIAA1429 and found that resistant cells responded more to cisplatin treatment after KIAA1429 depletion, while overexpression of KIAA1429 decreased the sensitivity. Moreover, we identified a putative p65 binding site on the promoter area of KIAA1429 and ChIP assay confirmed the binding. p65 depletion decreased the expression of KIAA1429. YTHDF1 is the most abundant m6A “reader” that interacts with m6A modified mRNA. Mechanistically, YTHDF1 was recruited to the 3′-untranslated Region (3′-UTR) of transcriptional factor, FOXM1 by KIAA1429 and stabilized FOXM1 mRNA. More importantly, KIAA1429 knockdown increased the sensitivity of resistant cells to cisplatin in vivo. In conclusion, our results demonstrated that KIAA1429 facilitated cisplatin resistance by stabilizing FOXM1 mRNA in gastric cancer cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

m6A Methyltransferase KIAA1429 Regulates the Cisplatin Sensitivity of Gastric Cancer Cells via Stabilizing FOXM1 mRNA

Zhu

Zhou

Chen

et al. 2022

Cancers

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“…The anti-inflammatory action of SSD might be ascribed to immediate suppression of these crucial inflammatory cytokines. A report has elucidated that SSD participates in the autophagic death of tumor cells via stimulating autophagosome formation [ 33 , 34 ]. Wang B et al .…”

Section: Discussionmentioning

confidence: 99%

Saikosaponin D alleviates inflammatory response of osteoarthritis and mediates autophagy via elevating microRNA-199-3p to target transcription Factor-4

Yan,

Zhang,

Yang

2024

J Orthop Surg Res

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Objective This study was to investigate the underlying mechanism by which Saikosaponin D (SSD) mitigates the inflammatory response associated with osteoarthritis (OA) and regulates autophagy through upregulation of microRNA (miR)-199-3p and downregulation of transcription Factor-4 (TCF4). Methods A mouse OA model was established. Mice were intragastrically administered with SSD (0, 5, 10 μmol/L) or injected with miR-199-3p antagomir into the knee. Then, pathological changes in cartilage tissues were observed. Normal chondrocytes and OA chondrocytes were isolated and identified. Chondrocytes were treated with SSD and/or transfected with oligonucleotides or plasmid vectors targeting miR-199-3p and TCF4. Cell viability, apoptosis, inflammation, and autophagy were assessed. miR-199-3p and TCF4 expressions were measured, and their targeting relationship was analyzed. Results In in vivo experiments, SSD ameliorated cartilage histopathological damage, decreased inflammatory factor content and promoted autophagy in OA mice. miR-199-3p expression was downregulated and TCF4 expression was upregulated in cartilage tissues of OA mice. miR-199-3p expression was upregulated and TCF4 expression was downregulated after SSD treatment. Downregulation of miR-199-3p attenuated the effect of SSD on OA mice. In in vitro experiments, SSD inhibited the inflammatory response and promoted autophagy in OA chondrocytes. Downregulation of miR-199-3p attenuated the effect of SSD on OA chondrocytes. In addition, upregulation of miR-199-3p alone inhibited inflammatory responses and promoted autophagy in OA chondrocytes. miR-199-3p targeted TCF4. Upregulation of TCF4 attenuated the effects of miR-199-3p upregulation on OA chondrocytes. Conclusions SSD alleviates inflammatory response and mediates autophagy in OA via elevating miR-199-3p to target TCF4.

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“…Additionally, SSD could enhance the chemosensitivity of cancer cells. For example, the administration of SSD could enhance the sensitivity of gastric cancer cells to cisplatin by inhibiting the IKKβ/NF-κB signaling pathway [14] . Tang et al proved that SSD enhanced the sensitivity of human non-small cell lung cancer (NSCLC) cells to cisplatin by inhibiting the STAT3/Bcl-2 pathway [15] .…”

Section: Introductionmentioning

confidence: 99%

Saikosaponin D Increases Temozolomide Sensitivity of Glioblastoma via ER Stress-Induced Apoptosis and Autophagy

Liu

Zheng

et al. 2023

Preprint

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Background: Glioblastoma multiforme (GBM) is a primary aggressive brain tumor with high morbidity and mortality. Temozolomide (TMZ) has been applied to the treatment of GBM for over a decade, but TMZ resistance is a major obstacle to preventing the recurrence of GBM after surgery. In this study, the effect of Saikosaponin D (SSD) on increasing TMZ sensitivity was investigated by activating the endoplasmic reticulum (ER) stresspathway. Methods: Three GBM cell lines with different sensitivities were selected, including rat RG-2 cells, human U251 cells, and LN-428 cells. Cell viability was detected by the Cell Counting Kit-8 (CCK-8) assay and the plate cloning assay method. Cell morphology was observed by hematoxylin and eosin (HE) staining. The apoptosis and autophagy of GBM cells were determined by Hoechst 33258 and MDC fluorescent staining. The expression and distribution of ER stress proteins (GRP78, CHOP, PERK and ATF6) were detected by Western blotting (WB) and immunocytochemistry (ICC). Meanwhile, the expression and distribution of apoptosis proteins (Caspase-12, Caspase-9, and Caspase-3) and autophagy proteins (Beclin-1 and LC3) were also examined by WB and ICC. Results: The CCK-8 proliferation experiment and HE staining results confirmed that TMZ could inhibit the proliferation of GBM cells with the increase of the treatment time and dose. The highest inhibition rate was observed in RG-2 cells, while LN-428 cells exhibited poor sensitivity. Besides, the combined treatment with SSD and TMZ (SSD+TMZ) significantly promoted the apoptosis of GBM cells, compared with single drug administration groups. In addition, the WB experiment results suggested that the expression of ER stress-related proteins (PERK, ATF6, GRP78, and CHOP) was up-regulated. Moreover, apoptotic bodies and damaged nuclei were observed under Hoechst 3328 staining in the SSD+TMZ treatment group. Furthermore, the WB results revealed that Caspase-3, Caspase-9, and Caspase-12 were cleaved, and the expression of these cleaved bodies was up-regulated after the SSD+TMZ treatment. Autophagosomes were observed under MDC staining, and the expression of autophagy proteins (LC3 and Beclin-1) was up-regulated. These results indicated that SSD enhanced TMZ sensitivity of GBM cells via ER stress-induced apoptosis and autophagy.

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Effects and Mechanisms of Saikosaponin D Improving the Sensitivity of Human Gastric Cancer Cells to Cisplatin

Cited by 18 publications

References 45 publications

m6A Methyltransferase KIAA1429 Regulates the Cisplatin Sensitivity of Gastric Cancer Cells via Stabilizing FOXM1 mRNA

m6A Methyltransferase KIAA1429 Regulates the Cisplatin Sensitivity of Gastric Cancer Cells via Stabilizing FOXM1 mRNA

Saikosaponin D alleviates inflammatory response of osteoarthritis and mediates autophagy via elevating microRNA-199-3p to target transcription Factor-4

Saikosaponin D Increases Temozolomide Sensitivity of Glioblastoma via ER Stress-Induced Apoptosis and Autophagy

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