DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin

Du, Jing; Wang, Tongtong; Li, Yanchun; Zhou, Yi; Wang, Xin; Yu, Xingxing; Ren, Xueying; An, Yihan; Wu, Yi Long; Sun, Weiyi; Fan, Weimin; Zhu, Qiaojuan; Wang, Ying; Tong, Xiangmin

doi:10.1016/j.freeradbiomed.2018.12.011

Cited by 353 publications

(253 citation statements)

References 43 publications

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“…Several artemisnin derivates have been demonstrated to kill cancer cells by inducing ferroptosis [14]. A few recent studies revealed DHA as ferroptosis inducer in cancer cells [19][20][21]. In consistent with these previous studies, our work demonstrated that DHA killed PLC cells by inducing ferroptosis (sFig.…”

Section: Discussionsupporting

confidence: 91%

“…Of note, treatment of DFOM or ferrostatin-1 does not completely abolish the anti-tumor effects of DHA, suggesting that triggering ferroptosis is not the only way for DHA to induce cytotoxicity in PLC cells. Although DHA has been shown to induce ferroptosis in other types of cancer cells [19][20][21], our work demonstrates such effects in PLC cells for the rst time.…”

Section: Discussionmentioning

confidence: 55%

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Dihydroartemisinin promotes CHAC1 transcription to induce ferroptosis in primary liver cancer cells: activation of unfolded protein responses

Wang¹,

Li²,

Liu³

et al. 2020

Preprint

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Background: This study aimed to explore whether dihydroartemisinin (DHA), an artemisinin derivate drug, eliminates primary liver cancer (PLC) cells by inducing ferroptosis. Methods: Four PLC cell lines were treated with varied concentrations of DHA. RNA interference was performed to knock down the expression of unfolded protein response (UPR) sensors in vitro. Results: DHA-caused PLC cell death was irrelevant to p53 status. PLC cells exposed to DHA displayed classic ferroptosis features – increased lipid ROS, MDA and iron ions, and decreased activity or expression of GSH, GPX4, SLC7A11 and SLC3A2. The anti-tumor effects of DHA were significantly weakened by ferrostatin-1 and deferoxamine mesylate salt, but augmented by iron overload. DHA activated all three UPR branches, including PERK/eIF2/ATF4, IRE1α / XBP1 , and ATF6, in vitro . Further, to deactivate UPRs, exclusive siRNA was used to silence the expression of ATF4, XBP1 or ATF6 in PLC cells. Unexpectedly, ferroptosis induced by DHA was significantly attenuated when ATF4, XBP1 or ATF6 was knocked down. The transcription of CHAC1, a molecule that is capable of degrading GSH, was enhanced by DHA, but weakened when the above three UPR transcription factors were silenced.Conclusion: DHA effectively induces ferroptosis in PLC cells, which involves the activation of anti-survival UPRs.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 55%

Dihydroartemisinin promotes CHAC1 transcription to induce ferroptosis in primary liver cancer cells: activation of unfolded protein responses

Wang¹,

Li²,

Liu³

et al. 2020

Preprint

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“…In Vitro. Ferroptosis is characterized by the accumulation of ROS, which is scavenged by GPX4 through conversion of reduced GSH into the oxidized form GSSG [24][25][26]. Therefore, the expression of GPX4 and the GSH level were explored and we found that IMCA significantly reduced GSH levels with negligible impact on the expression of GPX4 in DLD-1 and HCT116 cells (Figures 4(a) and 4(b); Fig.…”

Section: Imca Inhibited the Expression Of Slc7a11mentioning

confidence: 92%

“…In addition, the activity of SLC7A11 is inhibited by the mTORC pharmacological inhibitor rapamycin, which counteracts the elevated expression of SLC7A11 induced by APR246 and the protective cellular responses, leading to cell death [34]. Consistent with these two mechanisms, DHA induces the lethal ROS accumulation and ferroptosis of leukemia cells through the AMPK/mTOR pathway [25]. The present study showed that IMCA at 50 μM induced AMPK phosphorylation activation, mTOR dephosphorylation inhibition, and ultimately lethal ROS accumulation and ferroptosis in DLD-1 and HCT116 cells.…”

mentioning

confidence: 99%

IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal Cancer

Zhang

Liu

et al. 2020

Oxidative Medicine and Cellular Longevity

103

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Ferroptosis, implicated in several diseases, is a new form of programmed and nonapoptotic cell death triggered by iron-dependent lipid peroxidation after inactivation of the cystine/glutamate antiporter system xc–, which is composed of solute carrier family 7 membrane 11 (SLC7A11) and solute carrier family 3 membrane 2 (SLC3A2). Therefore, inducing ferroptosis through inhibiting the cystine/glutamate antiporter system xc– may be an effective way to treat cancer. In previous screening tests, we found that the benzopyran derivative 2-imino-6-methoxy-2H-chromene-3-carbothioamide (IMCA) significantly inhibited the viability of colorectal cancer cells. However, the impact of IMCA on ferroptosis remains unknown. Hence, this study investigated the effect of IMCA on ferroptosis and elucidated the underlying molecular mechanism. Results showed that IMCA significantly inhibited the cell viability of colorectal cancer cells in vitro and inhibited tumor growth with negligible organ toxicity in vivo. Further studies showed that IMCA significantly induced the ferroptosis of colorectal cancer cells. Mechanistically, IMCA downregulated the expression of SLC7A11 and decreased the contents of cysteine and glutathione, which resulted in reactive oxygen species accumulation and ferroptosis. Furthermore, overexpression of SLC7A11 significantly attenuated the ferroptosis caused by IMCA. In addition, IMCA regulated the activity of the AMPK/mTOR/p70S6k signaling pathway, which is related to the activity of SLC7A11 and ferroptosis. Collectively, our research provided experimental evidences on the activity and mechanism of ferroptosis induced by IMCA and revealed that IMCA might be a promising therapeutic drug for colorectal cancer.

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“…R. Kang et.al considered Beclin-1 is a key regulator of autophagy, can promote ferroptosis through a Beclin1-SLC7A11 complex 22 . The study showed that ferroptosis can be inhibited when knockout ATG7 23,24 . Torii S et al validated that autophagy is required for the induction of ferroptosis both in normal and cancer cells 25 .…”

Section: Discussionmentioning

confidence: 98%

Isoliquiritigenin attenuates LPS-induced acute kidney injury through suppression of HMGB1 pathway in renal tubular against ferritinophagy

Tang

Wang

et al. 2020

Preprint

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Septic acute kidney injury (AKI) mainly results in life-threatening renal dysfunction involving renal tubular injury to bring heavy burden to patients in intensive care unit (ICU). However, there is still a lack of therapy to prevent septic AKI effectively and inexpensive. To observe the role and novel mechanism of isoliquiritigenin (ISL) which isolated from the roots of licorice in septic AKI, we used LPS to induce renal tubular injury upon septic AKI both in vitro and in vivo. 50mg/kg ISL and 5 mg/kg Ferrostatin-1 were once given to the male C57BL/6 mice one hour before 1 mg/kg LPS i.p injection. 50 μM and 100 μM ISL respectively pre-treat the human renal tubular cells 5 hrs before 2 μg/ml LPS stimulation. We found ISL pretreatment apparently reversed LPS-induced renal dysfunction and ameliorated murine renal tubular injury by suppression HMGB1 pathway. Furthermore, we observed that LPS induced autophagy and ferroptosis in renal tubular, whereas ISL pretreatment significantly suppress autophagy and ferroptosis of renal tubular both in vitro and in vivo. Mechanically, autophagy activated ferroptosis via NCOA4-mediated ferritinophagy. Moreover, HMGB1 is required for ferritinophagy in renal tubular. ISL treatment inhibited the expression of HMGB1. Taken together, these results suggest that ISL protects LPS-induced acute kidney injury through suppression of HMGB1 pathway in renal tubular against ferritinophagy.

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DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin

Cited by 353 publications

References 43 publications

Dihydroartemisinin promotes CHAC1 transcription to induce ferroptosis in primary liver cancer cells: activation of unfolded protein responses

Dihydroartemisinin promotes CHAC1 transcription to induce ferroptosis in primary liver cancer cells: activation of unfolded protein responses

IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal Cancer

Isoliquiritigenin attenuates LPS-induced acute kidney injury through suppression of HMGB1 pathway in renal tubular against ferritinophagy

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