Abstract
Heat shock factor 1 (HSF1) is a powerful multifaceted oncogenic modifier that plays a role in maintaining the protein balance of cancer cells under various stresses. In recent studies, there have been reports of increased expression of HSF1 in colorectal cancer (CRC) cells, and the depletion of the HSF1 gene knockdown has inhibited colon cancer growth both in vivo and in vitro. Therefore, HSF1 is a promising target for colon cancer treatment and chemoprevention. In the present study, we found that Schizandrin A (Sch A) significantly inhibited the growth of CRC cell lines by inducing cell cycle arrest, apoptosis and death. Through HSE luciferase reporter assay and quantitative PCR (qPCR), we identified Sch A as a novel HSF1 inhibitor. In addition, Sch A could effectively inhibit the induction of HSF1 target proteins such as heat-shock protein (HSP) 70 (HSP70) and HSP27, whether in heat shock or normal temperature culture. In the Surface Plasmon Resonance (SPR) experiment, Sch A showed moderate affinity with HSF1, further confirming that Sch A might be a direct HSF1 inhibitor. The molecular docking and molecular dynamic simulation results of HSF1/Sch A suggested that Sch A formed key hydrogen bond and hydrophobic interactions with HSF1, which may contribute to its potent HSF1 inhibition. These findings provide clues for the design of novel HSF1 inhibitors and drug candidates for colon cancer treatment.
Highlights
Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related deaths worldwide [1]
The antiproliferative effects of Schizandrin A (Sch A) (Figure 1A) on four CRC cell lines RKO, DLD-1 SW620, SW480 and normal cell line CCD 841 CoN were determined through MTS assay
Sch A significantly inhibited the growth of CRC cells by inducing cell cycle arrest and apoptosis
Summary
Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related deaths worldwide [1]. Among all CRC cases, 75% of them are diagnosed at an early and localized stage, while the remaining patients have metastatic disease [3]. For these patients with unresectable CRC, the main method of drug therapy remains the use of chemotherapy regimens, such as 5-fluorouracil plus oxaliplatin or irinotecan (FOLFOX/FOLFIRI) [4]. After a few months of treatment, many patients inevitably develop acquired drug resistance, which greatly limits the clinical effectiveness of these targeted therapies [6,7]. It is urgent to discover more novel candidate targets for the clinical treatment of CRC
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