&lt;p&gt;High-dose vitamin C suppresses the invasion and metastasis of breast cancer cells via inhibiting epithelial-mesenchymal transition&lt;/p&gt;

Zeng, Ling‐Hui; Wang, Qingmei; Feng, Linqing; Ke, Yu-Dun; Xu, Qianyu; Wei, Anyi; Zhang, Chong; Ying, Rongbiao

doi:10.2147/ott.s222702

Cited by 36 publications

(44 citation statements)

References 39 publications

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“…Loss of extracellular matrix adhesion in primary cancer cells leads to intravasation, releasing CTCs. Studies suggested potential roles of vitamin C in preventing breast cancer metastasis via the regulation of the extracellular matrix [ 151 , 152 ]. An electron from vitamin C can be used to reduce ferric iron to ferrous iron, and this supports the action of lysyl hydroxylase and prolyl hydroxylase, iron binding enzymes required during collagen synthesis.…”

Section: Antioxidant and Breast Cancer Metastasismentioning

confidence: 99%

“…Transgenic mice lacking gulonolactone oxidase, a key enzyme for vitamin C synthesis, showed a poorly defined collagenous barrier, whereas vitamin C supplemented mice showed optimal extracellular matrix formation [ 151 , 153 ]. Treatment with a high (millimolar) concentration of vitamin C increased protein levels of E-cadherin, a key protein for cell-extracellular matrix adhesion in the BCap-37 human breast cancer cell [ 152 ]. Micromolar levels of vitamin C impaired the assembly of the actin filament via downregulation of YAP1, and this decreased motility of MDA-MB-231 cells [ 154 ].…”

Section: Antioxidant and Breast Cancer Metastasismentioning

confidence: 99%

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Cellular Mechanisms of Circulating Tumor Cells During Breast Cancer Metastasis

Park

Brown

Kim

2020

IJMS

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Circulating tumor cells (CTCs) are cancer cells that detach from the primary site and travel in the blood stream. A higher number of CTCs increases the risk of breast cancer metastasis, and it is inversely associated with the survival rates of patients with breast cancer. Although the numbers of CTCs are generally low and the majority of CTCs die in circulation, the survival of a few CTCs can seed the development of a tumor at a secondary location. An increasing number of studies demonstrate that CTCs undergo modification in response to the dynamic biophysical environment in the blood due in part to fluid shear stress. Fluid shear stress generates reactive oxygen species (ROS), triggers redox-sensitive cell signaling, and alters the function of intracellular organelles. In particular, the mitochondrion is an important target organelle in determining the metastatic phenotype of CTCs. In healthy cells, mitochondria produce adenosine triphosphate (ATP) via oxidative phosphorylation in the electron transport chain, and during oxidative phosphorylation, they produce physiological levels of ROS. Mitochondria also govern death mechanisms such as apoptosis and mitochondrial permeability transition pore opening to, in order eliminate unwanted or damaged cells. However, in cancer cells, mitochondria are dysregulated, causing aberrant energy metabolism, redox homeostasis, and cell death pathways that may favor cancer invasiveness. In this review, we discuss the influence of fluid shear stress on CTCs with an emphasis on breast cancer pathology, then discuss alterations of cellular mechanisms that may increase the metastatic potentials of CTCs.

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Section: Antioxidant and Breast Cancer Metastasismentioning

confidence: 99%

Section: Antioxidant and Breast Cancer Metastasismentioning

confidence: 99%

Cellular Mechanisms of Circulating Tumor Cells During Breast Cancer Metastasis

Park

Brown

Kim

2020

IJMS

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“…Several previous studies have reported that administration of a daily dose of 10 g L-AA has a beneficial effect in patients with cancer [28][29][30][31], while some have reported no overall relationship with L-AA intake [32][33][34]. Regarding this controversy, several reports have noted that the administration route of high-dose of L-AA (oral or intravenous injection) is crucial [35]. Intravenous injections of L-AA are maintained at high level in the blood [36,37].…”

Section: Introductionmentioning

confidence: 99%

L-Ascorbic Acid Inhibits Breast Cancer Growth by Inducing IRE/JNK/CHOP-Related Endoplasmic Reticulum Stress-Mediated p62/SQSTM1 Accumulation in the Nucleus

et al. 2020

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Anticancer effects of L-ascorbic acid (Vitamin C, L-AA) have been reported in various types of cancers. L-AA intake reduces breast cancer recurrence and mortality; however, the role of L-AA in the treatment of breast cancer remains poorly understood. In this study, we investigated the effect and mechanism action of L-AA on breast cancer growth. L-AA inhibited the growth of breast cancer cells by inducing apoptotic cell death at the evaluated treatment concentrations without affecting normal cells. Moreover, L-AA induces autophagosome formation via regulation of mammalian target of rapamycin (mTOR), Beclin1, and autophagy-related genes (ATGs) and increased autophagic flux. Notably, we observed that L-AA increased p62/SQSTM1 (sequestosome 1) protein levels. Accumulation of p62 protein in cancer cells in response to stress has been reported, but its role in cancer regulation remains controversial. Here, we demonstrated that L-AA-induced p62 accumulation is related to L-AA-induced breast cancer growth inhibition. Furthermore, L-AA induced endoplasmic reticulum (ER) stress via the IRE–JNK–CHOP (inositol-requiring endonuclease–c-Jun N-terminal kinase–C/EBP homologous protein) signaling pathways, which increased the nuclear levels of p62/SQSTM1. These findings provide evidence that L-AA-induced ER stress could be crucial for p62 accumulation-dependent cell death, and L-AA can be useful in breast cancer treatment.

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“…For example, oral vitamin C supplementation blocks murine breast cancer metastasis in Gulo knockout mice, which like humans, cannot synthesize vitamin C [6]. High doses of vitamin C via intraperitoneal injection inhibit metastasis of human breast cancer xenografts in nude mice [7], which, like the Gulo wild-type mice, maintain endogenous vitamin C at~50 µM in the plasma [8]. Our earlier work also showed that oral vitamin C supplementation blocks human triple-negative breast cancer (TNBC) xenograft metastasis in mice [9].…”

Section: Introductionmentioning

confidence: 99%

Vitamin C Inhibits Triple-Negative Breast Cancer Metastasis by Affecting the Expression of YAP1 and Synaptopodin 2

et al. 2019

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Vitamin C supplementation has been shown to decrease triple-negative breast cancer (TNBC) metastasis. However, the molecular mechanism whereby vitamin C inhibits metastasis remains elusive. It has been postulated that vitamin C reduces the levels of HIF-1α, the master regulator of metastasis, by promoting its hydroxylation and degradation. Here, we show that vitamin C at 100 µM, a concentration achievable in the plasma in vivo by oral administration, blocks TNBC cell migration and invasion in vitro. The protein level of HIF-1α remains largely unchanged in cultured TNBC cells and xenografts, partially due to its upregulated transcription by vitamin C, suggesting that HIF-1α unlikely mediates the action of vitamin C on metastasis. Vitamin C treatment upregulates the expression of synaptopodin 2 and downregulates the expression of the transcription coactivator YAP1, both genes in the Hippo pathway. The changes in SYNPO2 and YAP1 expression were subsequently validated at mRNA and protein levels in cultured TNBC cells and xenografts. Further experiments showed that vitamin C treatment inhibits F-actin assembly and lamellipodia formation, which correlates with the changes in SYNPO2 and YAP1 expression. Overall, these results suggest that vitamin C inhibits TNBC metastasis by affecting the expression of SYNPO2 and YAP1. Vitamin C may thus have a potential role in the prevention and treatment of TNBC metastasis.

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<p>High-dose vitamin C suppresses the invasion and metastasis of breast cancer cells via inhibiting epithelial-mesenchymal transition</p>

Cited by 36 publications

References 39 publications

Cellular Mechanisms of Circulating Tumor Cells During Breast Cancer Metastasis

Cellular Mechanisms of Circulating Tumor Cells During Breast Cancer Metastasis

L-Ascorbic Acid Inhibits Breast Cancer Growth by Inducing IRE/JNK/CHOP-Related Endoplasmic Reticulum Stress-Mediated p62/SQSTM1 Accumulation in the Nucleus

Vitamin C Inhibits Triple-Negative Breast Cancer Metastasis by Affecting the Expression of YAP1 and Synaptopodin 2

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