Bhardwaj Monika, Paul Souren, Jakhar Rekha, Khan Imran, Kang Ji In, Kim Ho Min, Yun Jong Won, Lee Seon-Jin, Cho Hee Jun, Lee Hee Gu, Kang Sun Chul
Department of Biotechnology, Daegu University, Kyoungsan, Kyoungbook, Republic of Korea.
Disease Molecule Biochemistry Laboratory, Graduate School of Medical Science and Engineering (GSMSE), KAIST, Yuseong-gu, Daejeon, Republic of Korea.
Oncotarget. 2017 Aug 10;8(68):112426-112441. doi: 10.18632/oncotarget.20113. eCollection 2017 Dec 22.
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 (). 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, 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.
热休克转录因子-1(HSF-1)保护癌细胞蛋白质组免受其恶劣肿瘤微环境所导致的蛋白质稳态改变的影响。与热休克蛋白的经典诱导情况不同,HSF-1的促癌活性仍有待探索。因此,由HSF-1调控的癌症脆弱的蛋白质稳态途径可能是天然化合物的潜在治疗靶点和新型生物标志物。牡荆素,一种天然黄酮类化合物,已被证明对多种细胞系具有强大的抗肿瘤作用。然而,在本研究中,当人结肠直肠癌HCT-116细胞暴露于牡荆素时,HSF-1下游靶蛋白如热休克蛋白的诱导受到抑制。我们确定HSF-1是牡荆素的潜在分子靶点,它与HSF-1的DNA结合结构域相互作用,抑制HSF-1的寡聚化和激活()。因此,由JNK作用介导的HSF-1过度磷酸化导致HSF-1转录失活,并支持ROS介导的自噬诱导。有趣的是,在HSF-1免疫沉淀和沉默的HCT-116细胞中,观察到载脂蛋白1(ApoL1)和JNK的共表达,其促进了不依赖半胱天冬酶的自噬性细胞死亡,伴有p62下调和LC3-I向LC3-II转化增加。最后,研究结果证实牡荆素在HCT-116异种移植模型中通过激活自噬级联反应抑制肿瘤生长。综上所述,我们的研究揭示了本研究中HSF-1和ApoL-1之间可能建立的新关联,这支持HSF-1作为牡荆素的潜在靶点以改善结直肠癌的治疗效果。