Vitexin confers HSF-1 mediated autophagic cell death by activating JNK and ApoL1 in colorectal carcinoma cells
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Monika Bhardwaj1, Souren Paul1, Rekha Jakhar1, Imran Khan1, Ji In Kang2, Ho Min Kim2, Jong Won Yun1, Seon-Jin Lee3,4, Hee Jun Cho3, Hee Gu Lee3,4 and Sun Chul Kang1
1Department of Biotechnology, Daegu University, Kyoungsan, Kyoungbook, Republic of Korea
2Disease Molecule Biochemistry Laboratory, Graduate School of Medical Science and Engineering (GSMSE), KAIST, Yuseong-gu, Daejeon, Republic of Korea
3Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
4Department of Biomolecular Science, University of Science and Technology (UST), Daejeon, Republic of Korea
Sun Chul Kang, email: [email protected]
Hee Gu Lee, email: [email protected]
Keywords: vitexin, HSF-1, ApoL1, autophagic cell death, colorectal carcinoma
Received: June 21, 2017 Accepted: July 25, 2017 Published: August 10, 2017
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.
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