Pivotal Role of Iron Homeostasis in the Induction of Mitochondrial Apoptosis by 6-Gingerol Through PTEN Regulated PD-L1 Expression in Embryonic Cancer Cells

Sp, Nipin; Kang, Dong Young; Jo, Eun Seong; J, Lee; Bae, Se Won; Jang, Kyoung‐Jin

doi:10.3389/fonc.2021.781720

Cited by 8 publications

(3 citation statements)

References 51 publications

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“…Recurrence of cancer is a major complication in various chemotherapeutic drugs because although it effectively suppresses tumor growth, it may fail to target CSCs [ 28 ]. This issue makes research on natural anticancer compounds an attractive method because such compounds can be used for long-term exposure as they reduce side effects and can help target both cancer cells and CSCs [ 29 , 30 ]. There are a few natural compounds that have the potential to work against CSCs [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

Antitumor Effects of Natural Bioactive Ursolic Acid in Embryonic Cancer Stem Cells

Kang

Jang

et al. 2022

Journal of Oncology

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Embryonic cancer cells (CSCs) could cause different types of cancer, a skill that makes them even more dangerous than other cancer cells. Identifying CSCs using natural products is a good option as it inhibits the recurrence of cancer with moderate various effects. Ursolic acid (UA) is a pentacyclic triterpenoid extracted from fruit and herbal remedies and has known anticancer functions against various cancer cells. However, its potential against CSCs remains uncertain. This study was planned to examine the induction of cell apoptosis by the UA. For cell signaling studies, we performed experiments, which are real-time qPCR and immunoblotting. Also, various cellular processes were analyzed using flow cytometry. The results raised a barrier to cell proliferation by the UA in NTERA-2 and NCCIT cells. Morphological studies also confirmed the UA’s ability to cause cell death in embryonic CSCs. Examination of cell death importation showed that the UA formed the expression of the iNOS and thus the cell generation and mitochondrial reactive oxygen generation, which created a reaction to cellular DNA damage by raising the protein levels of phospho-histone ATR and ATM. In addition, the UA created the binding of the G0/G1 cell cycle to NTERA-2 and NCCIT cells, improved the expression levels of p21 and p27, and reduced the expression levels of CDK4, cyclin D1, and cyclin E, confirming the UA’s ability to initiate cell cycle arrest. Finally, the UA created an internal mechanism of apoptosis in the embryonic CSC using BAX and cytochrome c regulation as well as the regulation of BCL-xL and BCL-2 proteins. Therefore, UA could be the best candidate for targeting CSCs and thus suppressing the emergence of cancer.

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Section: Discussionmentioning

confidence: 99%

Antitumor Effects of Natural Bioactive Ursolic Acid in Embryonic Cancer Stem Cells

Kang

Jang

et al. 2022

Journal of Oncology

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“…miR-21 is implicated in maintenance of the balance between Th17 and Treg cells in patients following gastric cancer resection via the PD-1/PD-L1 pathway [11]. Moreover, PTEN induction has been found to reduce miR-21 expression, thus resulting in downregulation of PD-L1 via the PI3K/Akt/ p53 signaling pathway in embryonic cancer stem cells [30]. Accordingly, our experimental results suggested that miR-21 induced PD-L1 expression via the PI3K/Akt pathway activation by targeting PDCD4 in BC cells.…”

Section: Discussionmentioning

confidence: 99%

Anti-PD-L1 Antibody Enhances T Cell Immune Responses and Reduces Resistance of Breast Cancer Cells to Radiotherapy

Guo

Ding

et al. 2022

Oxidative Medicine and Cellular Longevity

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Immune escape is a frequent occurrence, which limits the duration of antitumor immune responses to radiotherapy. Here, we aimed to ascertain the roles and underlying mechanisms of programmed death ligand 1 (PD-L1) in tolerance of breast cancer (BC) to radiotherapy. We first quantified microRNA-21 (miR-21) and PD-L1 expression in BC tissues and cells, followed by identification of the interactions between miR-21, PD-L1, and programmed cell death protein 4 (PDCD4). miR-21 knock-in mice were used to construct tumor-bearing models, which were then treated with anti-PD-L1 antibody and irradiation, followed by measurement of tumor growth and tumor immune escape. Finally, we evaluated the synergistic effects of radiotherapy and anti-PD-L1 antibody in vivo. The results showed increased miR-21 expression in BC tissues and cells, which was positively correlated with PD-L1 expression. The treatment with radiotherapy or anti-PD-L1 antibody in the miR-21 knock-in mice diminished tumor weight and volume, along with decreased CD3+CD8+ positive cells, serum IL-2 and IFN-γ levels, and lower PD-L1 expression, but augmented apoptosis of T and BC cells. Moreover, miR-21 significantly augmented PD-L1 expression via PI3K/Akt pathway activation by targeting PDCD4 in BC cells. Thus, radiotherapy and anti-PD-L1 antibody synergistically accelerated the therapeutic effect against BC in mice, thereby implicating a close interplay between radiotherapy, T cells, and the miR-21/PDCD4/PI3K/Akt/PD-L1 axis.

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“…MicroRNAs (miRNAs) can impede mRNA translation and increase mRNA breakdown, resulting in post-transcriptional gene expression changes. By interacting with PD-L1, these miRNAs also have a role in the tumor immune system [36]. As a result, miR-34a and miR-200c are linked to PD-L1 production in response to p53-dependent antitumor actions [37,38].…”

Section: Introductionmentioning

confidence: 99%

Anticancer Effects of 6-Gingerol through Downregulating Iron Transport and PD-L1 Expression in Non-Small Cell Lung Cancer Cells

Kang,

Park,

Song

et al. 2023

Cells

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Iron homeostasis is considered a key factor in human metabolism, and abrogation in the system could create adverse effects, including cancer. Moreover, 6-gingerol is a widely used bioactive phenolic compound with anticancer activity, and studies on its exact mechanisms on non-small cell lung cancer (NSCLC) cells are still undergoing. This study aimed to find the mechanism of cell death induction by 6-gingerol in NSCLC cells. Western blotting, real-time polymerase chain reaction, and flow cytometry were used for molecular signaling studies, and invasion and tumorsphere formation assay were also used with comet assay for cellular processes. Our results show that 6-gingerol inhibited cancer cell proliferation and induced DNA damage response, cell cycle arrest, and apoptosis in NSCLC cells, and cell death induction was found to be the mitochondrial-dependent intrinsic apoptosis pathway. The role of iron homeostasis in the cell death induction of 6-gingerol was also investigated, and iron metabolism played a vital role in the anticancer ability of 6-gingerol by downregulating EGFR/JAK2/STAT5b signaling or upregulating p53 and downregulating PD-L1 expression. Also, 6-gingerol induced miR-34a and miR-200c expression, which may indicate regulation of PD-L1 expression by 6-gingerol. These results suggest that 6-gingerol could be a candidate drug against NSCLC cells and that 6-gingerol could play a vital role in cancer immunotherapy.

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Pivotal Role of Iron Homeostasis in the Induction of Mitochondrial Apoptosis by 6-Gingerol Through PTEN Regulated PD-L1 Expression in Embryonic Cancer Cells

Cited by 8 publications

References 51 publications

Antitumor Effects of Natural Bioactive Ursolic Acid in Embryonic Cancer Stem Cells

Antitumor Effects of Natural Bioactive Ursolic Acid in Embryonic Cancer Stem Cells

Anti-PD-L1 Antibody Enhances T Cell Immune Responses and Reduces Resistance of Breast Cancer Cells to Radiotherapy

Anticancer Effects of 6-Gingerol through Downregulating Iron Transport and PD-L1 Expression in Non-Small Cell Lung Cancer Cells

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