{"title":"造血干细胞条件培养基通过HSP90和26S蛋白酶体系统的失调诱导结直肠癌干细胞凋亡","authors":"Sumit Mallick , Vanya Kadla Narayana , Akhila Balakrishna Rai , Shubham Sukerndeo Upadhyay , Thottethodi Subrahmanya Keshava Prasad , Sudheer Shenoy P , Bipasha Bose (Lead contact)","doi":"10.1016/j.biocel.2025.106773","DOIUrl":null,"url":null,"abstract":"<div><div>Cancer stem cells (CSCs) hold a significant role in cancer metastasis, high mortality and severity responsible for therapy resistance and tumour recurrence. The 26S proteasome system plays a major role in protein degradation in normal cells. As most cancers have upregulated 26S proteasome machinery, cancer cells use the 26S proteasome system in their favour for growth support by degrading unwanted proteins, but dysfunction of the 26S proteasome system induces apoptosis in cells. Here, we used hematopoietic stem cells (HSCs) and HSCs-derived conditioned media (CM) to target colorectal cancer stem cells (CRC-CSCs). HSCs are otherwise used extensively to save the lives of patients suffering from hematological malignancies and inherited blood disorders. HSCs-derived conditioned media contains various cytokines, chemokines, and secretory small molecules, which can also target the CRC-CSCs. Moreover, HSCs have exhibited CRC-CSC tropism in vitro in our pilot studies. As therapeutic uses of HSCs for targeting colorectal cancer (CRC) have never been reported, we hypothesized the CRC-CSC targeting properties of HSCs. Our results indicated altered protein function of CRC-CSCs upon co-culture with HSCs. Proteomics approaches showed that HSCs-CM disrupted 26S proteasomal complex and altered the mitochondrial bioenergetics, thereby activating apoptosis in CRC-CSCs. Furthermore, we observed that HSCs-CM significantly induced double-stranded DNA damage and proteasomal degradation, leading to apoptosis and upregulating the autophagy system. This study, hence, provides the prospective targeting of cancer stem cells using HSCs-CM, indicating a possible therapeutic approach.</div></div>","PeriodicalId":50335,"journal":{"name":"International Journal of Biochemistry & Cell Biology","volume":"184 ","pages":"Article 106773"},"PeriodicalIF":3.4000,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Hematopoietic stem cell conditioned media induces apoptosis in colorectal cancer stem cells via dysregulation of HSP90 and 26S proteasome system\",\"authors\":\"Sumit Mallick , Vanya Kadla Narayana , Akhila Balakrishna Rai , Shubham Sukerndeo Upadhyay , Thottethodi Subrahmanya Keshava Prasad , Sudheer Shenoy P , Bipasha Bose (Lead contact)\",\"doi\":\"10.1016/j.biocel.2025.106773\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Cancer stem cells (CSCs) hold a significant role in cancer metastasis, high mortality and severity responsible for therapy resistance and tumour recurrence. The 26S proteasome system plays a major role in protein degradation in normal cells. As most cancers have upregulated 26S proteasome machinery, cancer cells use the 26S proteasome system in their favour for growth support by degrading unwanted proteins, but dysfunction of the 26S proteasome system induces apoptosis in cells. Here, we used hematopoietic stem cells (HSCs) and HSCs-derived conditioned media (CM) to target colorectal cancer stem cells (CRC-CSCs). HSCs are otherwise used extensively to save the lives of patients suffering from hematological malignancies and inherited blood disorders. HSCs-derived conditioned media contains various cytokines, chemokines, and secretory small molecules, which can also target the CRC-CSCs. Moreover, HSCs have exhibited CRC-CSC tropism in vitro in our pilot studies. As therapeutic uses of HSCs for targeting colorectal cancer (CRC) have never been reported, we hypothesized the CRC-CSC targeting properties of HSCs. Our results indicated altered protein function of CRC-CSCs upon co-culture with HSCs. Proteomics approaches showed that HSCs-CM disrupted 26S proteasomal complex and altered the mitochondrial bioenergetics, thereby activating apoptosis in CRC-CSCs. Furthermore, we observed that HSCs-CM significantly induced double-stranded DNA damage and proteasomal degradation, leading to apoptosis and upregulating the autophagy system. This study, hence, provides the prospective targeting of cancer stem cells using HSCs-CM, indicating a possible therapeutic approach.</div></div>\",\"PeriodicalId\":50335,\"journal\":{\"name\":\"International Journal of Biochemistry & Cell Biology\",\"volume\":\"184 \",\"pages\":\"Article 106773\"},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2025-04-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Biochemistry & Cell Biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1357272525000408\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Biochemistry & Cell Biology","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1357272525000408","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Hematopoietic stem cell conditioned media induces apoptosis in colorectal cancer stem cells via dysregulation of HSP90 and 26S proteasome system
Cancer stem cells (CSCs) hold a significant role in cancer metastasis, high mortality and severity responsible for therapy resistance and tumour recurrence. The 26S proteasome system plays a major role in protein degradation in normal cells. As most cancers have upregulated 26S proteasome machinery, cancer cells use the 26S proteasome system in their favour for growth support by degrading unwanted proteins, but dysfunction of the 26S proteasome system induces apoptosis in cells. Here, we used hematopoietic stem cells (HSCs) and HSCs-derived conditioned media (CM) to target colorectal cancer stem cells (CRC-CSCs). HSCs are otherwise used extensively to save the lives of patients suffering from hematological malignancies and inherited blood disorders. HSCs-derived conditioned media contains various cytokines, chemokines, and secretory small molecules, which can also target the CRC-CSCs. Moreover, HSCs have exhibited CRC-CSC tropism in vitro in our pilot studies. As therapeutic uses of HSCs for targeting colorectal cancer (CRC) have never been reported, we hypothesized the CRC-CSC targeting properties of HSCs. Our results indicated altered protein function of CRC-CSCs upon co-culture with HSCs. Proteomics approaches showed that HSCs-CM disrupted 26S proteasomal complex and altered the mitochondrial bioenergetics, thereby activating apoptosis in CRC-CSCs. Furthermore, we observed that HSCs-CM significantly induced double-stranded DNA damage and proteasomal degradation, leading to apoptosis and upregulating the autophagy system. This study, hence, provides the prospective targeting of cancer stem cells using HSCs-CM, indicating a possible therapeutic approach.
期刊介绍:
IJBCB publishes original research articles, invited reviews and in-focus articles in all areas of cell and molecular biology and biomedical research.
Topics of interest include, but are not limited to:
-Mechanistic studies of cells, cell organelles, sub-cellular molecular pathways and metabolism
-Novel insights into disease pathogenesis
-Nanotechnology with implication to biological and medical processes
-Genomics and bioinformatics