Small-Molecule Gankyrin Inhibition as a Therapeutic Strategy for Breast and Lung Cancer

Kanabar, Dipti; Goyal, Mimansa; Kane, Emma I.; Chavan, Tejashri; Kabir, Abbas; Wang, Xuechun; Shukla, Snehal K.; Almasri, Joseph; Goswami, Sona; Osman, Gizem; Kokolis, Marino; Spratt, Donald E.; Gupta, Vivek; Muth, Aaron

doi:10.1021/acs.jmedchem.2c00190

Cited by 7 publications

(4 citation statements)

References 61 publications

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“…Evidence from studies on the transcriptional activity of the tumor suppressor gene p53 suggests that gankyrin has a negative regulatory effect on it 4 , 27 . To confirm this, we tested the effects of siRNA against gankyrin on the expression of p53 in Hs578T and MB-MDA-231 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Evidence has been presented to demonstrate its influence on multiple cancer-related pathways in various types of cancer. An elevation of gankyrin leads to the destruction of tumor suppressor proteins, resulting in an uncontrolled growth of cancer cells 27 . Our study revealed a significant increase in gankyrin expression in TNBC cells, indicating its critical role in the proliferation and growth of TNBC cells.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Gankyrin inhibits ferroptosis through the p53/SLC7A11/GPX4 axis in triple-negative breast cancer cells

Lei,

Zhang,

Huang

et al. 2023

Sci Rep

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Gankyrin is found in high levels in triple-negative breast cancer (TNBC) and has been established to form a complex with the E3 ubiquitin ligase MDM2 and p53, resulting in the degradation of p53 in hepatocarcinoma cells. Therefore, this study sought to determine whether gankyrin could inhibit ferroptosis through this mechanism in TNBC cells. The expression of gankyrin was investigated in relation to the prognosis of TNBC using bioinformatics. Co-immunoprecipitation and GST pull-down assays were then conducted to determine the presence of a gankyrin and MDM2 complex. RT-qPCR and immunoblotting were used to examine molecules related to ferroptosis, such as gankyrin, p53, MDM2, SLC7A11, and GPX4. Additionally, cell death was evaluated using flow cytometry detection of 7-AAD and a lactate dehydrogenase release assay, as well as lipid peroxide C11-BODIPY. Results showed that the expression of gankyrin is significantly higher in TNBC tissues and cell lines, and is associated with a poor prognosis for patients. Subsequent studies revealed that inhibiting gankyrin activity triggered ferroptosis in TNBC cells. Additionally, silencing gankyrin caused an increase in the expression of the p53 protein, without altering its mRNA expression. Co-immunoprecipitation and GST pull-down experiments indicated that gankyrin and MDM2 form a complex. In mouse embryonic fibroblasts lacking both MDM2 and p53, this gankyrin/MDM2 complex was observed to ubiquitinate p53, thus raising the expression of molecules inhibited by ferroptosis, such as SLC7A11 and GPX4. Furthermore, silencing gankyrin in TNBC cells disrupted the formation of the gankyrin/MDM2 complex, hindered the degradation of p53, increased SLC7A11 expression, impeded cysteine uptake, and decreased GPX4 production. Our findings suggest that TNBC cells are able to prevent cell ferroptosis through the gankyrin/p53/SLC7A11/GPX4 signaling pathway, indicating that gankyrin may be a useful biomarker for predicting TNBC prognosis or a potential therapeutic target.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Gankyrin inhibits ferroptosis through the p53/SLC7A11/GPX4 axis in triple-negative breast cancer cells

Lei,

Zhang,

Huang

et al. 2023

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Evidence has been presented to demonstrate its in uence on multiple cancer-related pathways in various types of cancer. An elevation of gankyrin leads to the destruction of tumor suppressor proteins, resulting in an uncontrolled growth of cancer cells 24 . Our study revealed a signi cant increase in gankyrin expression in TNBC cells, indicating its critical role in the proliferation and growth of TNBC cells.…”

Section: Discussionmentioning

confidence: 99%

“…Evidence from studies on the transcriptional activity of the tumor suppressor gene p53 suggests that gankyrin has a negative regulatory effect on it 4,24 . To con rm this, we tested the effects of siRNA against gankyrin on the expression of p53 in Hs578T and MB-MDA-231 cells.…”

Section: Gankyrin Negatively Regulates the Expression Of P53 In Tnbc ...mentioning

confidence: 99%

Gankyrin inhibits ferroptosis through the P53/SLC7A11/GPX4 axis in Triple-negative breast cancer cells

Lei,

Zhang,

Huang

et al. 2023

Preprint

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Gankyrin is found in high levels in triple-negative breast cancer (TNBC) and has been established to form a complex with the E3 ubiquitin ligase MDM2 and p53, resulting in the degradation of p53 in hepatocarcinoma cells. Therefore, this study sought to determine whether gankyrin could inhibit ferroptosis through this mechanism in TNBC cells. The expression of gankyrin was investigated in relation to the prognosis of TNBC using bioinformatics. Co-immunoprecipitation and GST pull-down assays were then conducted to determine the presence of a gankyrin and MDM2 complex. RT-qPCR and immunoblotting were used to examine molecules related to ferroptosis, such as gankyrin, p53, MDM2, SLC7A11, and GPX4. Additionally, cell death was evaluated using flow cytometry detection of 7-AAD and a lactate dehydrogenase release assay, as well as lipid peroxide C11-BODIPY. Results showed that the expression of gankyrin is significantly higher in TNBC tissues and cell lines,and is associated with a poor prognosis for patients. Subsequent studies revealed that inhibiting gankyrin activity triggered ferroptosis in TNBC cells. Additionally, silencing gankyrin caused an increase in the expression of the p53 protein, without altering its mRNA expression. Co-immunoprecipitation and GST pull-down experiments indicated that gankyrin and MDM2 form a complex. In mouse embryonic fibroblasts lacking both MDM2 and p53, this gankyrin/MDM2 complex was observed to ubiquitinate p53, thus raising the expression of molecules inhibited by ferroptosis, such as SLC7A11 and GPX4. Furthermore, silencing gankyrin in TNBC cells disrupted the formation of the gankyrin/MDM2 complex, hindered the degradation of p53, increased SLC7A11 expression, impeded cysteine uptake, and decreased GPX4 production. Our findings suggest that TNBC cells are able to prevent cell ferroptosis through the gankyrin/p53/SLC7A11/GPX4 signaling pathway, indicating that gankyrin may be a useful biomarker for predicting TNBC prognosis or a potential therapeutic target.

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Structural modification of the propyl linker of cjoc42 in combination with sulfonate ester and triazole replacements for enhanced gankyrin binding and anti-proliferative activity

Chavan,

Kanabar,

Patel

et al. 2024

Bioorganic & Medicinal Chemistry

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Small-Molecule Gankyrin Inhibition as a Therapeutic Strategy for Breast and Lung Cancer

Cited by 7 publications

References 61 publications

Gankyrin inhibits ferroptosis through the p53/SLC7A11/GPX4 axis in triple-negative breast cancer cells

Gankyrin inhibits ferroptosis through the p53/SLC7A11/GPX4 axis in triple-negative breast cancer cells

Gankyrin inhibits ferroptosis through the P53/SLC7A11/GPX4 axis in Triple-negative breast cancer cells

Structural modification of the propyl linker of cjoc42 in combination with sulfonate ester and triazole replacements for enhanced gankyrin binding and anti-proliferative activity

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