Abstract
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.
Highlights
Stem cells are known to differentiate into all types of tissues
We evaluated the status of embryonic cancer stem cells (CSCs) after Ursolic acid (UA) treatment using DAPI staining and observed a decrease in cell number in UA treatment (Figure 1(b)). e bright-field microscopic analysis confirmed the inhibition of NTERA-2 and NCCIT cell growth by UA treatment. ese results boosted the UA’s ability to prevent the proliferation of CSC
We analyzed the pathway underlying the apoptosis induction by UA, and our results were consistent with our expectations, as we observed an increase in BCL2-associated X (BAX) expression levels and a decrease in B-cell lymphoma 2 (BCL-2) and B-cell lymphoma-extra-large (BCLxL) after treatment with UA in embryonic CSCs, which suggested that UA induces mitochondrial apoptosis
Summary
Stem cells are known to differentiate into all types of tissues. Embryonic stem cells can differentiate all types of tissue present in the human body. External stimuli or alterations in gene expression may lead to CSC activation by Journal of Oncology angiogenesis, cell proliferation, and suppression of apoptosis, eventually resulting in tumor and metastasis [8]. Ursolic acid (UA) is a pentacyclic triterpenoid isolated from medicinal herbs and fruits with medicinal and biological functions [10] It has various anticancer properties such as induction of apoptosis, suppression of angiogenesis, inflammatory responses, antioxidation, and tumor metastasis. E ATM signaling activates the expression of tumor protein 53 (p53) in response to DNA damage leading to cell cycle arrest, DDR, and apoptosis mechanisms [22]. In the event of DNA damage, the CDK inhibitor, p21 (p21WAF1/Cip1), acts as a tumor suppressor in response and stimulates the cell cycle [23] It is known as a master effector of the tumor suppressor pathways due to its ability to inhibit p53-independent cell proliferation [24]. Is study demonstrated the induction of apoptosis by the UA in NTERA-2 and NCCIT embryonic CSCs, and the molecular mechanism underlying apoptosis induction by UA in embryonic cancer stem cells was analyzed
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