Hematopoietic stem cell conditioned media induces apoptosis in colorectal cancer stem cells via dysregulation of HSP90 and 26S proteasome system

Abstract

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.