A curcumin analogue GO‐Y030 depletes cancer stem cells by inhibiting the interaction between the HSP70/HSP40 complex and its substrates

• Published in: FEBS open bio Vol. 13; no. 3; pp. 434 - 446
• Main Authors: Suzuki, Maya, Yamamoto, Yohei, Nishijima‐Matsunobu, Aki, Kawasaki, Yohei, Shibata, Hiroyuki, Omori, Yasufumi
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.03.2023; John Wiley and Sons Inc; Wiley
• Subjects: Antibodies; Cancer; Cancer Stem Cells; Cancer Therapies; Cell Line, Tumor; Cloning; Curcumin; Curcumin - pharmacology; curcumin analogue; Denaturation; Drug resistance; Heat; Heat resistance; Heat shock proteins; High temperature; HSP40 Heat-Shock Proteins - metabolism; Hsp40 protein; HSP70 Heat-Shock Proteins - metabolism; HSP70 inhibitors; Hsp70 protein; Humans; Laboratories; Metastases; Neoplasm Recurrence, Local; Neoplastic Stem Cells - metabolism; Polypeptides; Protein folding; protein refolding; Reagents; Stem cells; stress response; Tumor cell lines; Tumors; United States > US; Japan; curcumin analogue; protein refolding; stress response; cancer stem cells; heat shock proteins; HSP70 inhibitors
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.13550

Cancer stem cells (CSCs) are proposed to be involved in tumor initiation and play important roles in cancer relapse, metastasis, and drug resistance. Therefore, the targeting of CSCs has potential for effective anticancer therapies. Curcumin is one of the most widely characterized phytochemicals with tumor‐suppressive potential. GO‐Y030 is a novel curcumin analogue exhibiting a much stronger growth‐inhibitory effect than curcumin. In the present study, we verified the potency of GO‐Y030 against a CSC population. We observed that GO‐Y030 suppressed CSC sphere‐forming ability in several cancer cell lines. Interestingly, a specific inhibitor of heat shock protein (HSP) 70 also exhibited effects similar to GO‐Y030 (i.e. inhibition of CSC sphere formation and upregulation of HSP70 and HSP40 protein expression), suggesting that HSP70 and/or HSP40 might be target molecules of GO‐Y030. We then performed an in vitro HSP70/HSP40‐mediated refolding activity assay and observed that chaperone activity was efficiently inhibited by GO‐Y030. Finally, we performed a substrate‐binding assay to show that GO‐Y030 reduced the binding of both HSP70 and HSP40 with their substrates. HSPs prevent denaturation or unfolding of client proteins under stressful conditions such as high temperature. Because CSCs by nature adapt to various stresses by reinforcing protein‐folding activity, the function of HSP70/HSP40 is important for the maintenance of CSC population. Our data suggest that GO‐Y030 may impair stress tolerance in CSCs by inhibiting the interaction of HSP70/HSP40 with their substrate proteins and disrupting the function of HSP70/HSP40, thereby contributing to a reduction of the CSC population. Cancer stem cells (CSCs) are, in general, under cellular stress because of the accumulation of unfolded and/or misfolded proteins, which are usually refolded by heat shock proteins (HSPs) such as HSP70‐1A, resulting in efficient survival of CSCs as an adaptive stress response. GO‐Y030, a curcumin analogue, directly impairs the unfolded protein response exerted by HSPs and causes failure of CSC self‐renewal.