Cucurbitacin E inhibits the Yes‑associated protein signaling pathway and suppresses brain metastasis of human non‑small cell lung cancer in a murine model

Hsu, Ping‐Chih; Tian, Bo; Yang, Yilin; Wang, Yucheng; Liu, Shu; Urisman, Anatoly; Yang, Cheng‐Ta; Xu, Zhidong; Jablons, David M.; Li, You

doi:10.3892/or.2019.7207

Cited by 20 publications

(25 citation statements)

References 44 publications

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“…Moreover, cucurbitacins B, E and I are shown to induce autophagy, however inhibition of autophagy can enhance cucurbitacin-induced apoptosis [481][482][483]. They also inhibit cell migration and invasion in human breast cancer MDA-MB-231 and SKBR3, NSCLC H2030-BrM3 and PC9-BrM3, and colorectal cancer COLO-205 cells [484][485][486][487], as well as angiogenesis in HUVECs [461,488].…”

Section: Cucurbitacinsmentioning

confidence: 99%

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

et al. 2019

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Numerous natural products originated from Chinese herbal medicine exhibit anti-cancer activities, including antiproliferative, pro-apoptotic, anti-metastatic, anti-angiogenic effects, as well as regulate autophagy, reverse multidrug resistance, balance immunity, and enhance chemotherapy in vitro and in vivo. To provide new insights into the critical path ahead, we systemically reviewed the most recent advances (reported since 2011) on the key compounds with anti-cancer effects derived from Chinese herbal medicine (curcumin, epigallocatechin gallate, berberine, artemisinin, ginsenoside Rg3, ursolic acid, silibinin, emodin, triptolide, cucurbitacin B, tanshinone I, oridonin, shikonin, gambogic acid, artesunate, wogonin, β-elemene, and cepharanthine) in scientific databases (PubMed, Web of Science, Medline, Scopus, and Clinical Trials). With a broader perspective, we focused on their recently discovered and/or investigated pharmacological effects, novel mechanism of action, relevant clinical studies, and their innovative applications in combined therapy and immunomodulation. In addition, the present review has extended to describe other promising compounds including dihydroartemisinin, ginsenoside Rh2, compound K, cucurbitacins D, E, I, tanshinone IIA and cryptotanshinone in view of their potentials in cancer therapy. Up to now, the evidence about the immunomodulatory effects and clinical trials of natural anti-cancer compounds from Chinese herbal medicine is very limited, and further research is needed to monitor their immunoregulatory effects and explore their mechanisms of action as modulators of immune checkpoints.

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Section: Cucurbitacinsmentioning

confidence: 99%

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

et al. 2019

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“…Low expression of the Hippo kinase LATS1 in addition to YAP overexpression have been identified in human NSCLC and are associated with poor prognosis [ 65 , 66 ]. Many previous studies have shown that YAP plays an important role in promoting the epithelial–mesenchymal transition (EMT), drug resistance, and metastasis in NSCLC [ 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ]. Moreover, the role of YAP in the cancer immunity of human NSCLC has recently been explored.…”

Section: Hippo/yap Singing Pathway In Nsclcmentioning

confidence: 99%

“…The same study also found that YAP protein expression could be rescued during the knockdown of ERK1/2 depletion through forced overexpression of the ERK2 gene [ 90 ]. In addition, several studies found that the activation of YAP increases the downstream gene expression of EGFR ligands such as amphiregulin (AREG) and neuregulin 1 (NRG-1), as well as connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (CYR61), forming an autocrine loop to reinforce the MAPK signaling pathway in order to induce drug resistance and cancer metastasis [ 75 , 76 , 94 , 95 , 96 , 97 ]. Therefore, YAP has been suggested to be involved in the promotion of resistance to therapies targeting the EGFR/Ras/Raf/MEK/ERK pathway, and it represents a therapeutic target for metastatic NSCLC.…”

Section: Hippo/yap Singing Pathway In Nsclcmentioning

confidence: 99%

“…The role of YAP in promoting NSCLC metastasis has been investigated in vivo, and the inhibition of YAP has shown promising efficacy in suppressing NSCLC metastasis in mouse models [ 74 , 75 , 76 ]. Dubois et al found that the tumor suppressor gene RASSF1A inhibits YAP through the GEF-H1/RhoB pathway, and they showed that RASSF1A depletion in a mouse model enhances the metastatic potential of the NSCLC cell line H1975 [ 74 ].…”

Section: Hippo/yap Singing Pathway In Nsclcmentioning

confidence: 99%

“…Additionally, a recent study showed that a biochemical natural compound, cucurbitacin E (a tetracyclic triterpene isolated from cucurbitaceae), inhibits YAP protein expression in H2030-BrM3 and PC9-BrM3 cells. Cucurbitacin E was also shown to suppress the brain metastasis of H2030-BrM3 cells in a mouse model [ 76 ]. Oxidative stress was reported to promote the migration, invasion, and metastasis of NSCLC through the LATS2/YAP signaling pathway in a recent study [ 101 ].…”

Section: Hippo/yap Singing Pathway In Nsclcmentioning

confidence: 99%

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The Crosstalk between Src and Hippo/YAP Signaling Pathways in Non-Small Cell Lung Cancer (NSCLC)

Hsu

Yang

Jablons

et al. 2020

Cancers

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The advancement of new therapies, including targeted therapies and immunotherapies, has improved the survival of non-small-cell lung cancer (NSCLC) patients in the last decade. Some NSCLC patients still do not benefit from therapies or encounter progressive disease during the course of treatment because they have intrinsic resistance, acquired resistance, or lack a targetable driver mutation. More investigations on the molecular biology of NSCLC are needed to find useful biomarkers for current therapies and to develop novel therapeutic strategies. Src is a non-receptor tyrosine kinase protein that interacts with cell surface growth factor receptors and the intracellular signaling pathway to maintain cell survival tumorigenesis in NSCLC. The Yes-associated protein (YAP) is one of the main effectors of the Hippo pathway and has been identified as a promoter of drug resistance, cancer progression, and metastasis in NSCLC. Here, we review studies that have investigated the activation of YAP as mediated by Src kinases and demonstrate that Src regulates YAP through three main mechanisms: (1) direct phosphorylation; (2) the activation of pathways repressing Hippo kinases; and (3) Hippo-independent mechanisms. Further work should focus on the efficacy of Src inhibitors in inhibiting YAP activity in NSCLC. In addition, future efforts toward developing potentially reasonable combinations of therapy targeting the Src–YAP axis using other therapies, including targeted therapies and/or immunotherapies, are warranted.

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Investigation of apoptotic effects of Cucurbitacin D, I, and E mediated by Bax/Bcl‐xL, caspase‐3/9, and oxidative stress modulators in HepG2 cell line

Üremiş,

Türköz,

Üremiş

2024

Drug Development Research

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Cucurbitacins, natural compounds highly abundant in the Cucurbitaceae plant family, are characterized by their anticancer, anti‐inflammatory, and hepatoprotective properties. These compounds have potential as therapeutic agents in the treatment of liver cancer. This study investigated the association of cucurbitacin D, I, and E (CuD, CuI, and CuE) with the caspase cascade, Bcl‐2 family, and oxidative stress modulators in the HepG2 cell line. We evaluated the antiproliferative effects of CuD, CuI, and CuE using the MTT assay. We analyzed Annexin V/PI double staining, cell cycle, mitochondrial membrane potential, and wound healing assays at different doses of the three compounds. To examine the modulation of the caspase cascade, we determined the protein and gene expression levels of Bax, Bcl‐xL, caspase‐3, and caspase‐9. We evaluated the total antioxidant status (TAS), total oxidant status (TOS), superoxide dismutase (SOD), glutathione (GSH), Total, and Native Thiol levels to measure cellular redox status. CuD, CuI, and CuE suppressed the proliferation of HepG2 cells in a dose‐dependent manner. The cucurbitacins induced apoptosis by increasing caspase‐3, caspase‐9, and Bax activity, inhibiting Bcl‐xL activation, causing loss of ΔΨm, and suppressing cell migration. Furthermore, cucurbitacins modulated oxidative stress by increasing TOS levels and decreasing SOD, GSH, TAS, and total and native Thiol levels. Our findings suggest that CuD, CuI, and CuE exert apoptotic effects on the hepatocellular carcinoma cell line by regulating Bax/Bcl‐xL, caspase‐3/9 signaling, and causing intracellular ROS increase in HepG2 cells.

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Cucurbitacin E inhibits the Yes‑associated protein signaling pathway and suppresses brain metastasis of human non‑small cell lung cancer in a murine model

Cited by 20 publications

References 44 publications

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

The Crosstalk between Src and Hippo/YAP Signaling Pathways in Non-Small Cell Lung Cancer (NSCLC)

Investigation of apoptotic effects of Cucurbitacin D, I, and E mediated by Bax/Bcl‐xL, caspase‐3/9, and oxidative stress modulators in HepG2 cell line

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