All-trans-retinoic Acid Modulates the Plasticity and Inhibits the Motility of Breast Cancer Cells

Zanetti, Adriana; Affatato, Roberta; Centritto, Floriana; Fratelli, Maddalena; Kurosaki, Mami; Barzago, Maria Monica; Bolis, Marco; Terao, Mineko; Garattini, Enrico; Paroni, Gabriela

doi:10.1074/jbc.m115.638510

Cited by 50 publications

(39 citation statements)

References 59 publications

(37 reference statements)

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“…In contrast to EMT inducers, atRA, known to also impair expression of drug transporters in hepatocytes in a major way [46], failed to reduce E-cadherin expression and to induce that of vimentin in HepaRG cells (Fig. 8A), which fully supports the fact that atRA does not favor EMT [47]. In addition, changes in profile of transporter mRNA expression induced by exposure to 5 µM atRA for 24 h, including down-regulation of OATP1B1 and OATP2B1 and up-regulation of NTCP and BCRP (Fig.…”

Section: Association Of Pma-induced Transporter Expression Changes Wisupporting

confidence: 69%

Protein kinase C-dependent regulation of human hepatic drug transporter expression

Mayati

Vée

Moreau

et al. 2015

Biochemical Pharmacology

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Hepatic drug transporters are now recognized as major actors of hepatobiliary elimination of drugs. Characterization of their regulatory pathways is therefore an important issue. In this context, the present study was designed to analyze the potential regulation of human hepatic transporter expression by protein kinase C (PKC) activation. Treatment by the reference PKC activator phorbol 12-myristate 13-acetate (PMA) for 48h was shown to decrease mRNA expression of various sinusoidal transporters, including OATP1B1, OATP2B1, NTCP, OCT1 and MRP3, but to increase that of OATP1B3, whereas mRNA expression of canalicular transporters was transiently enhanced (MDR1), decreased (BSEP and MRP2) or unchanged (BCRP) in human hepatoma HepaRG cells. The profile of hepatic transporter mRNA expression changes in PMA-treated HepaRG cells was correlated to that found in PMA-exposed primary human hepatocytes and was similarly observed in response to the PKC-activating marketed drug ingenol mebutate. It was associated with concomitant repression of OATP1B1 and OATP2B1 protein expression and reduction of OATP, OCT1, NTCP and MRP2 activity. The use of chemical PKC inhibitors further suggested a contribution of novel PKCs isoforms to PMA-mediated regulations of transporter mRNA expression. PMA was finally shown to cause epithelial-mesenchymal transition (EMT) in HepaRG cells and exposure to various additional EMT inducers, i.e., hepatocyte growth factor, tumor growth factor-1 or the HNF4 inhibitor BI6015, led to transporter expression alterations highly correlated to those triggered by PMA. Taken together, these data highlight PKC-dependent regulation of human hepatic drug transporter expression, which may be closely linked to EMT triggered by PKC activation.

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Section: Association Of Pma-induced Transporter Expression Changes Wisupporting

confidence: 69%

Protein kinase C-dependent regulation of human hepatic drug transporter expression

Mayati

Vée

Moreau

et al. 2015

Biochemical Pharmacology

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“…ATRA is the first example of a clinically useful cyto-differentiating agent to be used in the treatment of acute promyelocytic leukemia (23). Now it is proposed as an antitumor agent not only in the context of hematological malignancies but also the chemo-prevention and treatment of many cancers including HCC (8)(9)(10)(11). In addition, it has been reported that ATRA could be used as a chemopreventive agent to inhibit the progression of premalignant lesions of the breast (24,25).…”

Section: Discussionmentioning

confidence: 99%

“…However, the mechanisms underlying the effect of ATRA on HCC are largely unknown. It has been revealed that ATRA can induce mesenchymal to epithelial transition of HCT116 cells (10), while ATRA modulates epithelial-to-mesenchymal-transition of mammary tumor cells via the TGFβ and NOTCH pathways (11). Thus, we raised a hypothesis that the anti-HCC effect of ATRA might be closely related to the reverse process of EMT.…”

Section: Introductionmentioning

confidence: 93%

“…All-trans retinoic acid (ATRA), as a predominant natural metabolite of vitamin A, is involved in many important biological processes, including vision, morphogenesis, differentiation, growth, metabolism, and cellular homeostasis (7). ATRA is currently used to induce remission in patients with acute promyelocytic leukemia and has the potential for use in the treatment of solid tumors including HCC (8)(9)(10)(11). Many studies have reported that ATRA has anti-HCC ability.…”

Section: Introductionmentioning

confidence: 99%

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All-trans retinoic acid inhibits proliferation, migration, invasion and induces differentiation of hepa1-6 cells through reversing EMT in vitro

Cui

Gong

et al. 2015

International Journal of Oncology

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Hepatocellular carcinoma (HCC) has the characristics of tumor invasiveness, frequent intrahepatic spread and extra hepatic metastases, which affects the therapy efficiency and prognosis. Epithelial-mesenchymal transition (EMT) is now recognized as a key process in tumor invasion, metastasis and the generation of cancer initiating cells. All-trans retinoic acid (ATRA) is currently used as a potential chemo-therapeutic or chemo-preventive agent because of its anti-proliferative, pro-apoptotic and antioxidant properties. This study investigated the effects of ATRA at different concentrations on the proliferation, migration, invasion, differentiation and functions of the mouse hepa1-6 hepatocarcinoma cell line and explored whether ATRA regulates EMT in the antitumor process. Trypan blue staining and colony formation assay were used to detect cell proliferation. Wound-healing assay and Transwell Matrigel assay were performed to examine migration. Invasion was assessed by using Transwell invasion assay. In the present study, ATRA significantly inhibited the cell growth, colony formation, migration, and invasion capability of hepa1-6 cells in a dose-dependent manner. Furthermore, ATRA at low concentration (0.1 µmol/l) could generate these influences. After treated in the ATRA medium, the expression of mature hepatic markers ALB (albumin), CK18 (cytokeratin 18), TAT (tyrosine aminotransferase), ApoB (apolipoprotein B) decreased and that of hepatocarcinoma marker AFP (α fetoprotein) increased. At day 7 after ATRA induction, hepa1-6 cells showed comparable indocyanine green (ICG) uptake and glycogen storage function to the blank control. The mRNA expression of mesenchymal markers N-cadherin, vimentin, snail and twist decreased, while expression of epithelial marker E-cadherin increased in hepa1-6 cells after treated with ATRA. Therefore, this study demonstrates that ATRA remarkably suppressed the proliferation, migration, invasion of hepa1-6 hepatocarcinoma cell line and effectively induced its differentiation and liver functions in vitro through the reversal of EMT. HCC may be more sensitive to ATRA than other cancers, suggesting the prospective usefulness of ATRA in the treatment of HCC.

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“…It has shown that in HER2-positive SKBR3 and UACC812 cells, there is an amplification of the ERBB2 and RARA genes and ATRA activated a RARα-dependent epithelial differentiation program. Moreover, ATRA blocked Notch-1 up-regulation by EGF and/or heregulin-β1 and switches TGFβ from an EMT-inducing and pro-migratory determinant to an antimigratory mediator [67] . ATRA can reduce the MS-forming ability of a subset of breast cancer cells, which correlates with induction of apoptosis, reducing SOX2 expression and inducing of its antagonist CDX2.…”

Section: Retinoids and Breast Cancermentioning

confidence: 99%

Role of nuclear receptors in breast cancer stem cells

Papi

Orlandi

2016

WJSC

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The recapitulation of primary tumour heterogenity and the existence of a minor sub-population of cancer cells, capable of initiating tumour growth in xenografts on serial passages, led to the hypothesis that cancer stem cells (CSCs) exist. CSCs are present in many tumours, among which is breast cancer. Breast CSCs (BCSCs) are likely to sustain the growth of the primary tumour mass, as well as to be responsible for disease relapse and metastatic spreading. Consequently, BCSCs represent the most significant target for new drugs in breast cancer therapy. Both the hypoxic condition in BCSCs biology and proinflammatory cytokine network has gained increasing importance in the recent past. Breast stromal cells are crucial components of the tumours milieu and are a major source of inflammatory mediators. Recently, the antiinflammatory role of some nuclear receptors ligands has emerged in several diseases, including breast cancer. Therefore, the use of nuclear receptors ligands may be a valid strategy to inhibit BCSCs viability and consequently breast cancer growth and disease relapse.

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All-trans-retinoic Acid Modulates the Plasticity and Inhibits the Motility of Breast Cancer Cells

Cited by 50 publications

References 59 publications

Protein kinase C-dependent regulation of human hepatic drug transporter expression

Protein kinase C-dependent regulation of human hepatic drug transporter expression

All-trans retinoic acid inhibits proliferation, migration, invasion and induces differentiation of hepa1-6 cells through reversing EMT in vitro

Role of nuclear receptors in breast cancer stem cells

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