Carvedilol suppresses malignant proliferation of mammary epithelial cells through inhibition of the ROS‑mediated PI3K/AKT signaling pathway

Ma, Zhigui; Liu, Xingli; Zhang, Qiang; Yu, Zhengping; Gao, Dezong

doi:10.3892/or.2018.6873

Cited by 18 publications

(24 citation statements)

References 35 publications

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“…Two pathways known to be involved in skin carcinogenesis are UV-induced CPD formation (a DNA damage marker) and PGE 2 production (an inflammatory marker). Previously, it has been reported that carvedilol reduced DNA damage [7,8] and inflammation [11]. However, the data in the JB6 P+ cells and the 3D skin culture ( Figures 3A and 5A) were not as robust as the data obtained in mice [7].…”

Section: Discussionmentioning

confidence: 66%

“…Carvedilol is a receptor subtype non-selective β-blocker with α-AR blocking and antioxidant properties [3][4][5]. Recent data demonstrate that carvedilol prevents malignant transformation and carcinogenesis induced by epidermal growth factor (EGF), chemical carcinogens, and UV [6][7][8][9]. However, the cancer preventive mechanism for carvedilol remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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The β-Blocker Carvedilol Prevented Ultraviolet-Mediated Damage of Murine Epidermal Cells and 3D Human Reconstructed Skin

Chen

Liang

Shahid

et al. 2020

IJMS

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The β-blocker carvedilol prevents ultraviolet (UV)-induced skin cancer, but the mechanism is unknown. Since carvedilol possesses antioxidant activity, this study investigated whether carvedilol prevents oxidative photodamage of skin, a precursor event in skin carcinogenesis. The effects of carvedilol, metoprolol (a β-blocker without antioxidant property), and 4-hydroxycarbazole (4-OHC, a carvedilol synthesis intermediate and a free radical scavenger) were compared on UV- or H2O2-induced cell death and reactive oxygen species (ROS) production in murine epidermal JB6 P+ cells. Although carvedilol attenuated cell death, metoprolol and 4-OHC failed to show protective effects. As expected, increased cellular ROS induced by H2O2 or UV was abolished by carvedilol and 4-OHC, but not by metoprolol. Consistently, carvedilol attenuated the formation of UV-induced cyclobutane pyrimidine dimers (CPDs) and release of prostaglandin E2 in JB6 P+ cells. Carvedilol’s activity was further confirmed in full thickness 3D human reconstituted skin, where carvedilol attenuated UV-mediated epidermal thickening, the number of Ki-67 and p53 positive cells as well as CPD formation. Based on pathway-specific Polymerase Chain Reaction (PCR) Array analysis, carvedilol treatment in many cases normalized UV-induced expression changes in DNA repair genes. Thus, carvedilol’s photoprotective activity is not attributed to β-blockade or direct ROS-scavenging capacity, but likely via DNA repair regulation.

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Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

The β-Blocker Carvedilol Prevented Ultraviolet-Mediated Damage of Murine Epidermal Cells and 3D Human Reconstructed Skin

Chen

Liang

Shahid

et al. 2020

IJMS

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“…The amount of MECs within the mammary gland depends on their proliferation. The proteome dataset of BuMECs contained a large number of proteins associated with phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) (225 Proteins) 58 , mTOR (114 Proteins) 59 and nuclear factor-kappa β (NFK-β) (50 Proteins) 60 signalling pathways, which are reported to have a direct role in the proliferation of MECs. Synthesis and secretion of milk components are among the main functions of MECs.…”

Section: Discussionmentioning

confidence: 99%

In-depth proteome analysis of more than 12,500 proteins in buffalo mammary epithelial cell line identifies protein signatures for active proliferation and lactation

Jaswal

Anand

Kumar

et al. 2020

Sci Rep

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The mature mammary gland is made up of a network of ducts that terminates in alveoli. The innermost layer of alveoli is surrounded by the differentiated mammary epithelial cells (MECs), which are responsible for milk synthesis and secretion during lactation. However, the MECs are in a state of active proliferation during pregnancy, when they give rise to network like structures in the mammary gland. Buffalo (Bubalus bubalis) constitute a major source of milk for human consumption, and the MECs are the major precursor cells which are mainly responsible for their lactation potential. The proteome of MECs defines their functional state and suggests their role in various cellular activities such as proliferation and lactation. To date, the proteome profile of MECs from buffalo origin is not available. In the present study, we have profiled in-depth proteome of in vitro cultured buffalo MECs (BuMECs) during active proliferation using high throughput tandem mass spectrometry (MS). MS analysis identified a total of 8330, 5970, 5289, 4818 proteins in four sub-cellular fractions (SCFs) that included cytosolic (SCF-I), membranous and membranous organelle's (SCF-II), nuclear (SCF-III), and cytoskeletal (SCF-IV). However, 792 proteins were identified in the conditioned media, which represented the secretome. Altogether, combined analysis of all the five fractions (SCFs-I to IV, and secretome) revealed a total of 12,609 non-redundant proteins. The KEGG analysis suggested that these proteins were associated with 325 molecular pathways. Some of the highly enriched molecular pathways observed were metabolic, MAPK, PI3-AKT, insulin, estrogen, and cGMP-PKG signalling pathway. The newly identified proteins in this study are reported to be involved in NOTCH signalling, transport and secretion processes.The mammary gland, a unique organ of mammals, is a derivative of ventral skin 1 and has evolved to provide nutrition and immune protection to the offspring. Though the anatomical and physiological features of a mammary gland are diverse, the basic structure is similar in all species. The mature mammary gland is constituted by a network of tubular-alveolar structures, with their lumen lined by a layer of polarized secretory mammary epithelial cells (MECs). The MECs are dynamic components of the mammary gland, which undergo repeated rounds of proliferation and differentiation during different developmental stages such as pregnancy, and lactation 2 . The quantity and functional differentiation of MECs in the udder determine the milk-producing ability in livestock. Bovine (ruminants) are physiologically distinct from other mammals such as humans, mice and rats. The present study on in-depth proteome analysis of buffalo (Bubalus bubalis) MECs (BuMECs) advances our knowledge on the protein machinery operating in mammary gland development and lactogenesis in buffalo, which can be extrapolated in other mammalian species as well. Among the domestic livestock species, cattle (Bos taurus) and

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“…Activation of the PI3K/Akt pathways occurs in FSS-exposed cancer cells [ 38 , 81 , 82 ]. ROS generated during FSS [ 28 , 29 , 31 , 43 ] may signal activation of the PI3K/Akt pathway in breast cancer [ 83 , 84 , 85 ]. Application of a low level of FSS (1.8 dyn/cm 2 ) to MDA-MB-231 breast cancer cells increased phosphorylation of the regulatory subunit of PI3K, p85, followed by phosphorylation of the Ser 473 site of Akt [ 38 ].…”

Section: Cell Signaling Pathways In Circulating Tumor Cellsmentioning

confidence: 99%

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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Carvedilol suppresses malignant proliferation of mammary epithelial cells through inhibition of the ROS‑mediated PI3K/AKT signaling pathway

Cited by 18 publications

References 35 publications

The β-Blocker Carvedilol Prevented Ultraviolet-Mediated Damage of Murine Epidermal Cells and 3D Human Reconstructed Skin

The β-Blocker Carvedilol Prevented Ultraviolet-Mediated Damage of Murine Epidermal Cells and 3D Human Reconstructed Skin

In-depth proteome analysis of more than 12,500 proteins in buffalo mammary epithelial cell line identifies protein signatures for active proliferation and lactation

Cellular Mechanisms of Circulating Tumor Cells During Breast Cancer Metastasis

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