RIP1 and RIP3 contribute to shikonin-induced glycolysis suppression in glioma cells via increase of intracellular hydrogen peroxide

Lü, Bin; Wang, Zongqi; Ding, Ye; Wang, Xuanzhong; Lu, Shan; Wang, Chongcheng; He, Chuan; Piao, Meihua; Chi, Guangfan; Luo, Yan; Ge, Pengfei

doi:10.1016/j.canlet.2018.03.046

Cited by 40 publications

(31 citation statements)

References 46 publications

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“…Necroptosis regulated by RIP3 has been established as a new type of programmed cell death and could be induced in various cancer cells 35 , 36 . Consistent with previous reports 24 , 37 , RIP3 were found to be activated by shikonin in cisplatin resistant BC cells, which indicated that necroptosis is an alternative way to kill apoptosis resistant BC cells.…”

Section: Discussionsupporting

confidence: 93%

PKM2 Inhibitor Shikonin Overcomes the Cisplatin Resistance in Bladder Cancer by Inducing Necroptosis

Wang

Hao

Nan³

et al. 2018

Int. J. Biol. Sci.

131

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Cisplatin-based chemotherapy often results in the development of chemo-resistance when used to treat bladder cancer (BC), which is difficult to overcome. Recent data indicate that pyruvate kinase M2 (PKM2), a glycolytic enzyme for Warburg effect, is strongly upregulated in BC, and contributes to the cisplatin resistance in BC. However, the underlying mechanisms remain unclear. In this study, we also found that the expression level of PKM2 is also higher in cisplatin resistant BC cells and tumors. Down-regulation of PKM2 by siRNA or inhibition of PKM2 by shikonin re-sensitized the cisplatin resistant T24 cells. Shikonin and cisplatin together exhibit significantly greater killing effects than when used alone. Interestingly, we found shikonin kills the T24 cisplatin resistant cells by inducing necroptosis, as the cell death could not inhibited by apoptosis inhibitor, z-VAD, but compromised by RIP3 inhibitor, GSK872, or RIP3 siRNA. In contrast, shikonin induced apoptosis in T24 parental cells. We further investigate the underlying mechanism, and found that the dysregulation of Bcl-2 family proteins, including Bcl-2, PUMA, Bax, play an important role in deciding that shikonin kills the BC cells by necroptosis or apoptosis. Collectively, our results suggested that inducing necroptosis is an alternative way to overcome the apoptosis resistant in BC therapy, and orchestrating the regulation of Bcl-2, PUMA, and Bax in BC cisplatin resistant cells may improve the therapy effect of cisplatin in BC tumor.

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Section: Discussionsupporting

confidence: 93%

PKM2 Inhibitor Shikonin Overcomes the Cisplatin Resistance in Bladder Cancer by Inducing Necroptosis

Wang

Hao

Nan³

et al. 2018

Int. J. Biol. Sci.

131

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“…c-Myc down-regulation along with inhibition of ERK/JNK/ MAPK and Akt pathways are also involved in shikonininduced apoptosis and anti-proliferation in acute and chronic leukemia [618][619][620]. Moreover, the activation of necroptosis initiators, receptor interacting serine-threonine protein kinase (RIP) 1 and RIP3, by shikonin does not only contribute to DNA double strand breaks via ROS overproduction [621], but also facilitates glycolysis suppression via intracellular H 2 O 2 production [622]. In addition, shikonin induces cell cycle arrest through p21 and p27 up-regulation, cyclin and CDK down-regulation [605].…”

Section: Shikoninmentioning

confidence: 99%

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

et al. 2019

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Numerous natural products originated from Chinese herbal medicine exhibit anti-cancer activities, including antiproliferative, pro-apoptotic, anti-metastatic, anti-angiogenic effects, as well as regulate autophagy, reverse multidrug resistance, balance immunity, and enhance chemotherapy in vitro and in vivo. To provide new insights into the critical path ahead, we systemically reviewed the most recent advances (reported since 2011) on the key compounds with anti-cancer effects derived from Chinese herbal medicine (curcumin, epigallocatechin gallate, berberine, artemisinin, ginsenoside Rg3, ursolic acid, silibinin, emodin, triptolide, cucurbitacin B, tanshinone I, oridonin, shikonin, gambogic acid, artesunate, wogonin, β-elemene, and cepharanthine) in scientific databases (PubMed, Web of Science, Medline, Scopus, and Clinical Trials). With a broader perspective, we focused on their recently discovered and/or investigated pharmacological effects, novel mechanism of action, relevant clinical studies, and their innovative applications in combined therapy and immunomodulation. In addition, the present review has extended to describe other promising compounds including dihydroartemisinin, ginsenoside Rh2, compound K, cucurbitacins D, E, I, tanshinone IIA and cryptotanshinone in view of their potentials in cancer therapy. Up to now, the evidence about the immunomodulatory effects and clinical trials of natural anti-cancer compounds from Chinese herbal medicine is very limited, and further research is needed to monitor their immunoregulatory effects and explore their mechanisms of action as modulators of immune checkpoints.

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“…The mice were cared in accordance with the guidelines for experimental animals of Jilin University and the study was approved by the ethics committee of First Hospital of Jilin University (Changchun, China). The animal quantity used in this study was estimated as described previously 20 . A total of 1 × 10 7 logarithmically growing C6 cells in 100 μL of PBS were subcutaneously injected into the right flank of each mouse.…”

Section: Rat C6 Tumor Xenograft In Micementioning

confidence: 99%

Autophagy activated by silibinin contributes to glioma cell death via induction of oxidative stress-mediated BNIP3-dependent nuclear translocation of AIF

Wang

et al. 2020

Cell Death Dis

Self Cite

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Induction of lethal autophagy has become a strategy to eliminate glioma cells, but it remains elusive whether autophagy contributes to cell death via causing mitochondria damage and nuclear translocation of apoptosis inducing factor (AIF). In this study, we find that silibinin induces AIF translocation from mitochondria to nuclei in glioma cells in vitro and in vivo, which is accompanied with autophagy activation. In vitro studies reveal that blocking autophagy with 3MA, bafilomycin A1 or by knocking down ATG5 with SiRNA inhibits silibinin-induced mitochondrial accumulation of superoxide, AIF translocation from mitochondria to nuclei and glioma cell death. Mechanistically, silibinin activates autophagy through depleting ATP by suppressing glycolysis. Then, autophagy improves intracellular H 2 O 2 via promoting p53-mediated depletion of GSH and cysteine and downregulation of xCT. The increased H 2 O 2 promotes silibinin-induced BNIP3 upregulation and translocation to mitochondria. Knockdown of BNIP3 with SiRNA inhibits silibinin-induced mitochondrial depolarization, accumulation of mitochondrial superoxide, and AIF translocation from mitochondria to nuclei, as well as prevents glioma cell death. Furthermore, we find that the improved H 2 O 2 reinforces silibinin-induced glycolysis dysfunction. Collectively, autophagy contributes to silibinininduced glioma cell death via promotion of oxidative stress-mediated BNIP3-dependent nuclear translocation of AIF.

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RIP1 and RIP3 contribute to shikonin-induced glycolysis suppression in glioma cells via increase of intracellular hydrogen peroxide

Cited by 40 publications

References 46 publications

PKM2 Inhibitor Shikonin Overcomes the Cisplatin Resistance in Bladder Cancer by Inducing Necroptosis

PKM2 Inhibitor Shikonin Overcomes the Cisplatin Resistance in Bladder Cancer by Inducing Necroptosis

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

Autophagy activated by silibinin contributes to glioma cell death via induction of oxidative stress-mediated BNIP3-dependent nuclear translocation of AIF

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