Physalin A regulates the Nrf2 pathway through ERK and p38 for induction of detoxifying enzymes

Shin, Ji Min; Lee, Kyung-Mi; Lee, Hee Ju; Yun, Ji Ho; Nho, Chu Won

doi:10.1186/s12906-019-2511-y

Cited by 41 publications

(26 citation statements)

References 36 publications

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“…These data suggest that the genus Physalis is an important source of withanolide-type molecules with potential therapeutic effect against human diseases [9]. Studies have demonstrated anti-tumor and anti-inflammatory properties of Physalin A. Nrf2 pathway was regulated by physalin A through ERK and p38 for induction of detoxifying enzymes [10]. Physalin A was shown to induce apoptosis and protective autophagy in HT1080 human fibrosarcoma cells [7].…”

Section: Introductionmentioning

confidence: 87%

Physalin A, 13,14-Seco-16, 24-Cyclo-Steroid, Inhibits Stemness of Breast Cancer Cells by Regulation of Hedgehog Signaling Pathway and Yes-Associated Protein 1 (YAP1)

Choi

Liu

et al. 2021

IJMS

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The Hedgehog (HH) signaling pathway plays an important role in embryonic development and adult organ homeostasis. Aberrant activity of the Hedgehog signaling pathway induces many developmental disorders and cancers. Recent studies have investigated the relationship of this pathway with various cancers. GPCR-like protein Smoothened (SMO) and the glioma-associated oncogene (GLI1) are the main effectors of Hedgehog signaling. Physalin A, a bioactive substance derived from Physalis alkekengi, inhibits proliferation and migration of breast cancer cells and mammospheres formation. Physalin A-induced apoptosis and growth inhibition of mammospheres, and reduced transcripts of cancer stem cell (CSC) marker genes. Physalin A reduced protein expressions of SMO and GLI1/2. Down-regulation of SMO and GLI1 using siRNA inhibited mammosphere formation. Physalin A reduced mammosphere formation by reducing GLI1 gene expression. Down-regulation of GLI1 reduced CSC marker genes. Physalin A reduced protein level of YAP1. Down-regulation of YAP1 using siRNA inhibited mammosphere formation. Physalin A reduced mammosphere formation through reduction of YAP1 gene expression. Down-regulation of YAP1 reduced CSC marker genes. We showed that treatment of MDA-MB-231 breast cancer cells with GLI1 siRNA induced inhibition of mammosphere formation and down-regulation of YAP1, a Hippo pathway effector. These results show that Hippo signaling is regulated by the Hedgehog signaling pathway. Physalin A also inhibits the canonical Hedgehog and Hippo signaling pathways, CSC-specific genes, and the formation of mammospheres. These findings suggest that physalin A is a potential therapeutic agent for targeting CSCs.

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Section: Introductionmentioning

confidence: 87%

Physalin A, 13,14-Seco-16, 24-Cyclo-Steroid, Inhibits Stemness of Breast Cancer Cells by Regulation of Hedgehog Signaling Pathway and Yes-Associated Protein 1 (YAP1)

Choi

Liu

et al. 2021

IJMS

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“…For example, the growth of A549 cells was inhibited by physalin A through cell cycle arrest in the G2/M phase [23]. The expression of detoxifying enzymes was also increased by physalin A by upregulating the Nrf2 pathway in HepG2 cells [24]. The growth of breast and lung cancer cells was inhibited by Physalin B through cell cycle arrest [25][26][27][28].…”

Section: Discussionmentioning

confidence: 99%

Physalis alkekengi L. var. francheti alleviates neuronal cell death caused by activated microglia in vitro

Park

Kwon²,

Kim³

et al. 2021

Appl Biol Chem

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Microglia are the macrophages that reside in the brain. Activated microglia induces further activation of astrocytes and neuronal cells for mounting an immune response. However, activated microglia release neurotoxic mediators causing neuroinflammation, which is associated with chronic etiology of neurodegenerative diseases. We investigated the effect of ethanol extract of Physalis alkekengi L. var. francheti fruit (PAFE) on neuronal cell death mediated by activated microglia. PAFE decreased NO production and IL-6 secretion in LPS-stimulated BV-2 and primary microglial cells without reducing cell viability. Consistently, treatment with PAFE decreased iNOS and COX-2 expression and ERK phosphorylation in LPS-stimulated BV-2 cells. Finally, apoptosis of N2a cells grown in conditioned media prepared from LPS-stimulated BV-2 cells containing PAFE was inhibited via downregulation of the Bax/Bcl-2 ratio. Taken together, PAFE alleviates neuronal cell death by reducing neurotoxic mediators such as NO and IL-6 from activated microglia. Therefore, it could be a potential candidate to treat neurodegenerative diseases caused by chronic neuroinflammation.

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“…Under normal conditions, Nrf2 is bound to Keap1, and when cells are exposed to stress, the dimer is split and Nrf2 targets the nucleus to activate the expression of genes related to the antioxidant response [ 61 ]. It is described that the separation of Nrf2 and Keap1 occurs through the phosphorylation of Nrf2, caused by ERK and p38 [ 62 ]. NFE2L2 is the gene that encodes Nrf2 and it is basally more expressed in Hs766T than in the rest of pancreatic and colorectal carcinoma and glioblastoma cell lines ( Figure 7 A).…”

Section: Discussionmentioning

confidence: 99%

Cell Death Mechanisms Induced by CLytA-DAAO Chimeric Enzyme in Human Tumor Cell Lines

Fuentes-Baile

García-Morales

Pérez-Valenciano

et al. 2020

IJMS

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The combination of the choline binding domain of the amidase N-acetylmuramoyl-L-alanine (CLytA)-D-amino acid oxidase (DAAO) (CLytA-DAAO) and D-Alanine induces cell death in several pancreatic and colorectal carcinoma and glioblastoma cell lines. In glioblastoma cell lines, CLytA-DAAO-induced cell death was inhibited by a pan-caspase inhibitor, suggesting a classical apoptotic cell death. Meanwhile, the cell death induced in pancreatic and colon carcinoma cell lines is some type of programmed necrosis. In this article, we studied the mechanisms that trigger CLytA-DAAO-induced cell death in pancreatic and colorectal carcinoma and glioblastoma cell lines and we acquire a further insight into the necrotic cell death induced in pancreatic and colorectal carcinoma cell lines. We have analyzed the intracellular calcium mobilization, mitochondrial membrane potential, PARP-1 participation and AIF translocation. Although the mitochondrial membrane depolarization plays a crucial role, our results suggest that CLytA-DAAO-induced cell death is context dependent. We have previously detected pancreatic and colorectal carcinoma cell lines (Hs766T and HT-29, respectively) that were resistant to CLytA-DAAO-induced cell death. In this study, we have examined the putative mechanism underlying the resistance in these cell lines, evaluating both detoxification mechanisms and the inflammatory and survival responses. Overall, our results provide a better understanding on the cell death mechanism induced by CLytA-DAAO, a promising therapy against cancer.

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Physalin A regulates the Nrf2 pathway through ERK and p38 for induction of detoxifying enzymes

Cited by 41 publications

References 36 publications

Physalin A, 13,14-Seco-16, 24-Cyclo-Steroid, Inhibits Stemness of Breast Cancer Cells by Regulation of Hedgehog Signaling Pathway and Yes-Associated Protein 1 (YAP1)

Physalin A, 13,14-Seco-16, 24-Cyclo-Steroid, Inhibits Stemness of Breast Cancer Cells by Regulation of Hedgehog Signaling Pathway and Yes-Associated Protein 1 (YAP1)

Physalis alkekengi L. var. francheti alleviates neuronal cell death caused by activated microglia in vitro

Cell Death Mechanisms Induced by CLytA-DAAO Chimeric Enzyme in Human Tumor Cell Lines

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