{"title":"抑制Sox4通过P38信号通路增加耐药黑色素瘤细胞对顺铂的敏感性","authors":"Cheng Qiong, Zuo Fuguo","doi":"10.2174/0113862073231734231102074936","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>SRY-Box Transcription Factor 4 (Sox4) has been found to be overexpressed in a number of malignancies and is linked to medication resistance. The underlying mechanism of Sox4 in cisplatin-resistant melanomas, however, remains unknown.</p><p><strong>Methods: </strong>Immunohistochemistry (IHC) was used to examine the expression of Sox4 in melanoma, pigmented nevi, and normal skin tissue. Induction in vitro was used to create the cisplatin- resistant cell lines SK-MEL-28R and A375R. The CCK8 test was used to determine the IC50 values of cisplatin-resistant cells. Lentivirus shut down Sox4 in SK-MEL-28R and A375R cells. The Affymetrix GeneChip array was then utilized to detect changes in signaling pathways in SK-MEL-28R interfering with Sox4. Western blot, qRT-PCR, flow cytometry, and a caspase 3 activity kit were used to confirm the biological process of Sox4 impacting cisplatin resistance in melanoma.</p><p><strong>Results: </strong>Sox4 expression in melanoma was substantially higher than in pigmented nevus and normal skin tissue (p<0.05, p<0.01).SK-MEL-28R and A375R melanoma cisplatin-resistant strains were created effectively. They were 12.6 and 10.2 times more resistant to cisplatin, respectively than the parental cells. P-gp protein expression was substantially higher in cisplatinresistant strains than in parental strains. Sox4 inhibition lowered the IC50 value of cisplatin in resistant cells. (The IC50 value of SK-MEL-28R+NC was 122.7 mg/L and 24.4 mg/L for SKMEL- 28R+sh-sox4; the IC50 value of A375R+NC was 40.55 mg/L and 5.99 mg/L for A375R+sh-sox4). Meanwhile, Sox4 knockdown causes S phase arrest and enhanced caspase-3 activity in cisplatin-resistant melanoma cells. Sox4 knockdown led to activation of the P38 signaling pathway in resistant cells, according to genome-wide expression analysis, qRT-PCR, and Western blot detection.</p><p><strong>Conclusion: </strong>Our findings imply that inhibiting Sox4 can improve the sensitivity of drugresistant melanoma cells to cisplatin via the P38 signaling pathway, thus opening up a new route for melanoma treatment.</p>","PeriodicalId":10491,"journal":{"name":"Combinatorial chemistry & high throughput screening","volume":" ","pages":""},"PeriodicalIF":1.6000,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Inhibition of Sox4 Increases the Sensitivity of Drug-resistant Melanoma Cells to Cisplatin through the P38 Signaling Pathway.\",\"authors\":\"Cheng Qiong, Zuo Fuguo\",\"doi\":\"10.2174/0113862073231734231102074936\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>SRY-Box Transcription Factor 4 (Sox4) has been found to be overexpressed in a number of malignancies and is linked to medication resistance. The underlying mechanism of Sox4 in cisplatin-resistant melanomas, however, remains unknown.</p><p><strong>Methods: </strong>Immunohistochemistry (IHC) was used to examine the expression of Sox4 in melanoma, pigmented nevi, and normal skin tissue. Induction in vitro was used to create the cisplatin- resistant cell lines SK-MEL-28R and A375R. The CCK8 test was used to determine the IC50 values of cisplatin-resistant cells. Lentivirus shut down Sox4 in SK-MEL-28R and A375R cells. The Affymetrix GeneChip array was then utilized to detect changes in signaling pathways in SK-MEL-28R interfering with Sox4. Western blot, qRT-PCR, flow cytometry, and a caspase 3 activity kit were used to confirm the biological process of Sox4 impacting cisplatin resistance in melanoma.</p><p><strong>Results: </strong>Sox4 expression in melanoma was substantially higher than in pigmented nevus and normal skin tissue (p<0.05, p<0.01).SK-MEL-28R and A375R melanoma cisplatin-resistant strains were created effectively. They were 12.6 and 10.2 times more resistant to cisplatin, respectively than the parental cells. P-gp protein expression was substantially higher in cisplatinresistant strains than in parental strains. Sox4 inhibition lowered the IC50 value of cisplatin in resistant cells. (The IC50 value of SK-MEL-28R+NC was 122.7 mg/L and 24.4 mg/L for SKMEL- 28R+sh-sox4; the IC50 value of A375R+NC was 40.55 mg/L and 5.99 mg/L for A375R+sh-sox4). Meanwhile, Sox4 knockdown causes S phase arrest and enhanced caspase-3 activity in cisplatin-resistant melanoma cells. Sox4 knockdown led to activation of the P38 signaling pathway in resistant cells, according to genome-wide expression analysis, qRT-PCR, and Western blot detection.</p><p><strong>Conclusion: </strong>Our findings imply that inhibiting Sox4 can improve the sensitivity of drugresistant melanoma cells to cisplatin via the P38 signaling pathway, thus opening up a new route for melanoma treatment.</p>\",\"PeriodicalId\":10491,\"journal\":{\"name\":\"Combinatorial chemistry & high throughput screening\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":1.6000,\"publicationDate\":\"2025-05-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Combinatorial chemistry & high throughput screening\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2174/0113862073231734231102074936\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"BIOCHEMICAL RESEARCH METHODS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Combinatorial chemistry & high throughput screening","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2174/0113862073231734231102074936","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}
Inhibition of Sox4 Increases the Sensitivity of Drug-resistant Melanoma Cells to Cisplatin through the P38 Signaling Pathway.
Background: SRY-Box Transcription Factor 4 (Sox4) has been found to be overexpressed in a number of malignancies and is linked to medication resistance. The underlying mechanism of Sox4 in cisplatin-resistant melanomas, however, remains unknown.
Methods: Immunohistochemistry (IHC) was used to examine the expression of Sox4 in melanoma, pigmented nevi, and normal skin tissue. Induction in vitro was used to create the cisplatin- resistant cell lines SK-MEL-28R and A375R. The CCK8 test was used to determine the IC50 values of cisplatin-resistant cells. Lentivirus shut down Sox4 in SK-MEL-28R and A375R cells. The Affymetrix GeneChip array was then utilized to detect changes in signaling pathways in SK-MEL-28R interfering with Sox4. Western blot, qRT-PCR, flow cytometry, and a caspase 3 activity kit were used to confirm the biological process of Sox4 impacting cisplatin resistance in melanoma.
Results: Sox4 expression in melanoma was substantially higher than in pigmented nevus and normal skin tissue (p<0.05, p<0.01).SK-MEL-28R and A375R melanoma cisplatin-resistant strains were created effectively. They were 12.6 and 10.2 times more resistant to cisplatin, respectively than the parental cells. P-gp protein expression was substantially higher in cisplatinresistant strains than in parental strains. Sox4 inhibition lowered the IC50 value of cisplatin in resistant cells. (The IC50 value of SK-MEL-28R+NC was 122.7 mg/L and 24.4 mg/L for SKMEL- 28R+sh-sox4; the IC50 value of A375R+NC was 40.55 mg/L and 5.99 mg/L for A375R+sh-sox4). Meanwhile, Sox4 knockdown causes S phase arrest and enhanced caspase-3 activity in cisplatin-resistant melanoma cells. Sox4 knockdown led to activation of the P38 signaling pathway in resistant cells, according to genome-wide expression analysis, qRT-PCR, and Western blot detection.
Conclusion: Our findings imply that inhibiting Sox4 can improve the sensitivity of drugresistant melanoma cells to cisplatin via the P38 signaling pathway, thus opening up a new route for melanoma treatment.
期刊介绍:
Combinatorial Chemistry & High Throughput Screening (CCHTS) publishes full length original research articles and reviews/mini-reviews dealing with various topics related to chemical biology (High Throughput Screening, Combinatorial Chemistry, Chemoinformatics, Laboratory Automation and Compound management) in advancing drug discovery research. Original research articles and reviews in the following areas are of special interest to the readers of this journal:
Target identification and validation
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Label-free detection technologies and applications
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Probe discovery and development, hit to lead optimization
Combinatorial chemistry (e.g. small molecules, peptide, nucleic acid or phage display libraries)
Chemical library design and chemical diversity
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Bipharmaceutical studies of Natural products
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Laboratory automation, robotics, microfluidics, signal detection technologies
Current & Future Institutional Research Profile
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