Abstract
Heat shock transcription factor-1 (HSF-1) guards the cancerous cells proteome against the alterations in protein homeostasis generated by their hostile tumor microenvironment. Contrasting with the classical induction of heat shock proteins, the pro-oncogenic activities of HSF-1 remains to be explored. Therefore, cancer's fragile proteostatic pathway governed by HSF-1 could be a potential therapeutic target and novel biomarker by natural compounds. Vitexin, a natural flavonoid has been documented as a potent anti-tumor agent on various cell lines. However, in the present study, when human colorectal carcinoma HCT-116 cells were exposed to vitexin, the induction of HSF-1 downstream target proteins, such as heat shock proteins were suppressed. We identified HSF-1 as a potential molecular target of vitexin that interact with DNA-binding domain of HSF-1, which inhibited HSF-1 oligomerization and activation (in silico). Consequently, HSF-1 hyperphosphorylation mediated by JNK operation causes transcriptional inactivation of HSF-1, and supported ROS-mediated autophagy induction. Interestingly, in HSF-1 immunoprecipitated and silenced HCT-116 cells, co-expression of apolipoprotein 1 (ApoL1) and JNK was observed which promoted the caspase independent autophagic cell death accompanied by p62 downregulation and increased LC3-I to LC3-II conversion. Finally, in vivo findings confirmed that vitexin suppressed tumor growth through activation of autophagic cascade in HCT-116 xenograft model. Taken together, our study insights a probable novel association between HSF-1 and ApoL-1 was established in this study, which supports HSF-1 as a potential target of vitexin to improve treatment outcome in colorectal cancer.
Highlights
Cells encounter stress from various environmental cues which causes profound alterations in proteome homeostasis known as proteotoxic stress
Tumor cells treated with vitexin caused remarkable changes with majority of cells to become shrink and show distorted morphology characteristics of programmed cell death (Figure 1B), with significant cell death as evidenced by reduction in cell viability and enhanced lactate dehydrogenase (LDH) activity (Figure 1C, 1D)
The repertoire of Heat shock transcription factor-1 (HSF-1)-regulated genes in cancer www.impactjournals.com/oncotarget extends far beyond protein folding, which includes from energy metabolism to extracellular matrix formation
Summary
Cells encounter stress from various environmental cues which causes profound alterations in proteome homeostasis known as proteotoxic stress. They are well equipped with sophisticated adaptive mechanisms to combat these stresses. HSF-1 accumulates in the nucleus, oligomerizes and become transcriptionally active to increase Hsps and other cytoprotective target gene levels to survive proteotoxic www.impactjournals.com/oncotarget stress. HSF-1 is constitutively active in cancer cells and plays a multifaceted role in carcinogenesis, including expression of atypical levels of Hsps, malignant transformation, and others, identified as a biomarker for cancer prognosis [5, 6]
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