Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer

Ouyang, Shumin; Li, Huaxuan; Lou, Linlin; Huang, Qiuyao; Zhang, Zhenhua; Mo, Jianshan; Li, Min; Lu, Jiaye; Zhu, Kai; Chu, Yunjie; Ding, Wen; Zhu, Jianzheng; Lin, Ziyou; Zx, Lin; Wang, Junjian; Yue, Peibin; Turkson, James; Liu, Peiqing; Wang, Yuanxiang; Zhang, Xiaolei

doi:10.1016/j.redox.2022.102317

Cited by 179 publications

(112 citation statements)

References 64 publications

(78 reference statements)

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“…STAT3 has been previously reported to negatively regulate ferroptosis [ 21 ], and the activation of the JAK2/STAT3 signaling pathway has been reported to inhibit P53 expression [ 22 ]. Thus, we explored the regulatory effect of the JAK2/STAT3 signaling pathway toward P53, which is involved in AMPK-mediated GPX4-dependent ferroptosis.…”

Section: Resultsmentioning

confidence: 99%

Energy-Stress-Mediated AMPK Activation Promotes GPX4-Dependent Ferroptosis through the JAK2/STAT3/P53 Axis in Renal Cancer

Zhang

Qiu

et al. 2022

Oxidative Medicine and Cellular Longevity

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Energy stress is an unfavorable condition that tumor cells are often exposed to. Ferroptosis is considered an emerging target for tumor therapy. However, the role of ferroptosis in energy stress in renal cancer is currently unknown. In this study, we found that glucose deprivation significantly enhanced GPX4-dependent ferroptosis through AMPK activation. Further, AMPK activation suppressed GPX4 expression at the transcriptional level through the upregulation of P53 expression. Additionally, the inactivation of JAK2/STAT3 transcriptionally promoted P53 expression, thereby promoting AMPK-mediated GPX4-dependent ferroptosis. In conclusion, energy stress promotes AMPK-mediated GPX4-dependent erastin-induced ferroptosis in renal cancer through the JAK2/STAT3/P53 signaling axis.

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Section: Resultsmentioning

confidence: 99%

Energy-Stress-Mediated AMPK Activation Promotes GPX4-Dependent Ferroptosis through the JAK2/STAT3/P53 Axis in Renal Cancer

Zhang

Qiu

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…The HCC cell lines Huh7, Hep3B, and HepG2, treated with 5 µM of sorafenib [ 16 ], resulted in cell death, while the use of the ferroptosis inhibitors liproxstatin-1 (Liprox-1) [ 17 ] and deferoxamine mesylate (DFO) [ 18 ] significantly rescued sorafenib-induced cell death ( Figure 1 A). Changes in cell morphology, including the rounding-up of cells and their subsequent death, were observed in sorafenib-treated HCC cells ( Figure 1 B).…”

Section: Resultsmentioning

confidence: 99%

SHP-1/STAT3-Signaling-Axis-Regulated Coupling between BECN1 and SLC7A11 Contributes to Sorafenib-Induced Ferroptosis in Hepatocellular Carcinoma

Huang

Chen

et al. 2022

IJMS

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Ferroptosis is a type of iron-dependent cell death pertaining to an excess of lipid peroxidation. It has been suggested that sorafenib—an anti-angiogenic medication for hepatocellular carcinoma (HCC)—induces ferroptosis, but the underlying mechanism for this remains largely unknown. We employed siRNA-mediated gene silencing to investigate the role of Src homology region 2 domain-containing phosphatase-1 (SHP-1), following sorafenib treatment, in cystine/glutamate-antiporter-system-Xc−-regulated cystine uptake. Co-immunoprecipitation was also performed to examine the interactions between MCL1, beclin 1 (BECN1), and solute carrier family 7 member 11 (SLC7A11), which functions as the catalytic subunit of system Xc−. The results of this study showed that sorafenib enhanced the activity of SHP-1, dephosphorylated STAT3, downregulated the expression of MCL1 and, consequently, reduced the association between MCL1 and BECN1. In contrast, increased binding between BECN1 and SLC7A11 was observed following sorafenib treatment. The elevated interaction between BECN1 and SLC7A11 inhibited the activity of system Xc−, whereas BECN1 silencing restored cystine intake and protected cells from ferroptosis. Notably, ectopic expression of MCL1 uncoupled BECN1 from SLC7A11 and rescued cell viability by attenuating lipid peroxidation. The results revealed that ferroptosis could be induced in HCC via SHP-1/STAT3-mediated downregulation of MCL1 and subsequent inhibition of SLC7A11 by increased BECN1 binding.

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“…51 Recently, we also validated that STAT3 represents a promising therapeutic target for gastric cancer. 52 Promising STAT3 inhibitors as drug candidates for gastric cancer are still needed. Therefore, as an initial screening, compound 7 was evaluated for its cell growth inhibitory activity in a cell viability assay against gastric cancer cell lines that express constitutively active STAT3, including AGS and MGC-803.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Boronic Acid: A Novel Pharmacophore Targeting Src Homology 2 (SH2) Domain of STAT3

Deng

Zhang

et al. 2022

J. Med. Chem.

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SH2 domains have been recognized as promising targets for various human diseases. However, targeting SH2 domains with phosphopeptides or small-molecule inhibitors derived from bioisosteres of the phosphate group is still challenging. Identifying novel bioisosteres of the phosphate group to achieve favorable in vivo potency is urgently needed. Here, we report the feasibility of targeting the STAT3-SH2 domain with a boronic acid group and the identification of a highly potent inhibitor compound 7 by replacing the carboxylic acid of compound 4 with a boronic acid. Compound 7 shows higher binding affinity, better cellular potency, more favorable PK profiles, and higher in vivo antitumor activity than 4. The stronger anticancer effect of 7 partially stems from its covalent binding mode with the SH2 domain, verified by the washout experiments. The relatively high level of sequence conservation among SH2 domains makes the results presented here of general significance.

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Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer

Cited by 179 publications

References 64 publications

Energy-Stress-Mediated AMPK Activation Promotes GPX4-Dependent Ferroptosis through the JAK2/STAT3/P53 Axis in Renal Cancer

Energy-Stress-Mediated AMPK Activation Promotes GPX4-Dependent Ferroptosis through the JAK2/STAT3/P53 Axis in Renal Cancer

SHP-1/STAT3-Signaling-Axis-Regulated Coupling between BECN1 and SLC7A11 Contributes to Sorafenib-Induced Ferroptosis in Hepatocellular Carcinoma

Boronic Acid: A Novel Pharmacophore Targeting Src Homology 2 (SH2) Domain of STAT3

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