Curcumin Analog Go-Y030 Diminishes Cancer Stem Cell Population By Inhibiting Interaction Of Hsp70 With Its Substrates

It has been established that a cancer tissue contains, in general, a small subpopulation of cancer stem cells (CSCs) having tumor initiation capacity. Because CSCs are resistant to chemoradiotherapy and play important roles in cancer relapse and metastasis, strategies targeting CSCs are crucial for effective anticancer therapies. Curcumin (diferuloylmethane) isolated from the rhizome of the plant turmeric (Curcuma longa) is one of the most widely characterized phytochemicals and well known to suppress cancer cell proliferation, invasion, angiogenesis, and metastasis by regulating multiple cell signaling pathways. However, its bioavailability is limited due to poor absorption. To improve this disadvantage, Ohori et al. (Mol Cancer Ther 2006;5:2563-71.) synthesized a new curcumin analog GO-Y030 (1,5-bis(3,5-bis(methoxymethoxy)phenyl)-1,4-pentadiene-3-one), which has an about 30-fold greater growth-inhibitory effect than curcumin. In the current study, we verified the potency of GO-Y030 to act against CSC population. We first discovered that GO-Y030 could dose-dependently suppress a sphere-forming ability in human HuH7 hepatocellular carcinoma and human PC3 prostatic carcinoma cell lines. Interestingly, the specific inhibitor of the stress-inducible heat shock protein (HSP) 70 (also called HSP72, HSP70-1, or HSPA1A) exhibited effects similar to GO-Y030, i.e., inhibition of CSC sphere formation and upregulation of HSP70 and HSP40 protein expression. As this result suggested that target molecules of GO-Y030 might be HSP70 and its co-chaperones such as HSP40, we next performed in vitro HSP70/HSP40-mediated refolding activity assay and revealed that GO-Y030 efficiently inhibited HSP70/HSP40 chaperone activity. Finally, performing the substrate-binding assay, we have proven that GO-Y030 reduces the substrate-recognition and binding activity of HSP70. HSPs are molecular chaperones that function to prevent denaturation or unfolding of client proteins when they are threatened by stress or high temperature. Since CSCs by nature adapt to oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress by enhancing synthesis of protein-folding chaperones, the function of HSP70/HSP40 is important for the maintenance of CSC population. Our data suggest that GO-Y030 should impair stress tolerance in CSCs by inhibiting the interaction of HSP70 with substrate proteins and disrupting the function of HSP70/HSP40 and thus should finally contribute to reduction of CSC population. Citation Format: Maya Suzuki, Yohei Yamamoto, Aki Nishijima, Hiroyuki Shibata, Yasufumi Omori. Curcumin analog GO-Y030 diminishes cancer stem cell population by inhibiting interaction of HSP70 with its substrates [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6377.