Vitexin confers HSF-1 mediated autophagic cell death by activating JNK and ApoL1 in colorectal carcinoma cells

// Monika Bhardwaj 1 , Souren Paul 1 , Rekha Jakhar 1 , Imran Khan 1 , Ji In Kang 2 , Ho Min Kim 2 , Jong Won Yun 1 , Seon-Jin Lee 3, 4 , Hee Jun Cho 3 , Hee Gu Lee 3, 4 and Sun Chul Kang 1 1 Department of Biotechnology, Daegu University, Kyoungsan, Kyoungbook, Republic of Korea 2 Disease Molecule Biochemistry Laboratory, Graduate School of Medical Science and Engineering (GSMSE), KAIST, Yuseong-gu, Daejeon, Republic of Korea 3 Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea 4 Department of Biomolecular Science, University of Science and Technology (UST), Daejeon, Republic of Korea Correspondence to: Sun Chul Kang, email: sckang@daegu.ac.kr Hee Gu Lee, email: hglee@kribb.re.kr Keywords: vitexin, HSF-1, ApoL1, autophagic cell death, colorectal carcinoma Received: June 21, 2017      Accepted: July 25, 2017      Published: August 10, 2017 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.