miR-29b sensitizes multiple myeloma cells to bortezomib-induced apoptosis through the activation of a feedback loop with the transcription factor Sp1

Amodio, Nicola; Martino, Maria Teresa Di; Foresta, Umberto; Leone, Emanuela; Lionetti, Marta; Leotta, Marzia; Gullà, Annamaria; Pitari, Maria Rita; Conforti, Francesco; Rossi, Marco; Agosti, Valter; Fulciniti, Mariateresa; Misso, Gabriella; Morabito, Fortunato; Ferrarini, Manlio; Neri, Antonino; Caraglia, Michele; Munshi, Nikhil C.; Anderson, Kenneth C.; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

doi:10.1038/cddis.2012.175

Cited by 142 publications

(151 citation statements)

References 57 publications

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“…Peripheral blood mononuclear cells (PBMC), bone marrow mononuclear cells (BMMNC), and primary cells from multiple myeloma patient bone marrow aspirates, following informed consent and University Magna Graecia (Catanzaro, Italy) IRB approval, were isolated using Ficoll-Hypaque density gradient sedimentation as reported previously (4). Multiple myeloma patient cells were separated from bone marrow samples by antibody-mediated selection using anti-CD138 magnetic-activated cell separation microbeads (Miltenyi Biotec).…”

Section: Multiple Myeloma Cell Lines Primary Cells and Reagentsmentioning

confidence: 99%

Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma

Amodio

Stamato

Gullà

et al. 2016

Molecular Cancer Therapeutics

100

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Epigenetic abnormalities are common in hematologic malignancies, including multiple myeloma, and their effects can be efficiently counteracted by a class of tumor suppressor miRNAs, named epi-miRNAs. Given the oncogenic role of histone deacetylases (HDAC) in multiple myeloma, we investigated whether their activity could be antagonized by miR-29b, a well-established epi-miRNA. We demonstrated here that miR-29b specifically targets HDAC4 and highlighted that both molecules are involved in a functional loop. In fact, silencing of HDAC4 by shRNAs inhibited multiple myeloma cell survival and migration and triggered apoptosis and autophagy, along with the induction of miR-29b expression by promoter hyperacetylation, leading to the downregulation of prosurvival miR-29b targets (SP1, MCL-1). Moreover, treatment with the pan-HDAC inhibitor SAHA upregulated miR-29b, overcoming the negative control exerted by HDAC4. Importantly, overexpression or inhibition of miR-29b, respectively, potentiated or antagonized SAHA activity on multiple myeloma cells, as also shown in vivo by a strong synergism between miR-29b synthetic mimics and SAHA in a murine xenograft model of human multiple myeloma. Altogether, our results shed light on a novel epigenetic circuitry regulating multiple myeloma cell growth and survival and open new avenues for miR-29b-based epi-therapeutic approaches in the treatment of this malignancy. Mol Cancer Ther; 15(6); 1364-75. Ó2016 AACR.

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Section: Multiple Myeloma Cell Lines Primary Cells and Reagentsmentioning

confidence: 99%

Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma

Amodio

Stamato

Gullà

et al. 2016

Molecular Cancer Therapeutics

100

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“…Analysis of apoptosis Cells were treated as previously described with ionizing radiation, FTY720, or combinations; after 24 h, cells were harvested, washed twice with cold 1× PBS and stained with Annexin V-PE/7-aminoactinomycin D (7AAD) solution (BD Bioscience) as indicated by the manufacturer 41 and then analyzed by flow cytometery (FACS-Calibur, BD Bioscience).…”

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confidence: 99%

Sphingosine analog fingolimod (FTY720) increases radiation sensitivity of human breast cancer cells in vitro

Marvaso

Barone

Amodio

et al. 2014

Cancer Biology & Therapy

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Radiotherapy is one of the most effective therapeutic strategies for breast cancer patients, although its efficacy may be reduced by intrinsic radiation resistance of cancer cells. Recent investigations demonstrate a link between cancer cell radio-resistance and activation of sphingosine kinase (SphK1), which plays a key role in the balance of lipid signaling molecules. Sphingosine kinase (SphK1) activity can alter the sphingosine-1-phosphate (S1P)/ceramide ratio leading to an imbalance in the sphingolipid rheostat. Fingolimod (FTY720) is a novel sphingosine analog and a potent immunosuppressive drug that acts as a SphK1 antagonist, inhibits the growth, and induces apoptosis in different human cancer cell lines. We sought to investigate the in vitro radiosensitizing effects of FTY720 on the MDA-MB-361 breast cancer cell line and to assess the effects elicited by radiation and FTY720 combined treatments. We found that FTY720 significantly increased anti-proliferative and pro-apoptotic effects induced by a single dose of ionizing radiation while causing autophagosome accumulation. At the molecular level, FTY720 significantly potentiated radiation effects on perturbation of signaling pathways involved in regulation of cell cycle and apoptosis, such as PI3K/AKT and MAPK. In conclusion, our data highlight a potent radiosensitizing effect of FTY720 on breast cancer cells and provide the basis of novel therapeutic strategies for breast cancer treatment

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“…GATA3 increased the activity of the miR29b promoter, and deletion of the GATA sites diminished GATA3-mediated reporter induction, demonstrating that these sites are necessary for the expression of miR-29b (Chou et al, 2013). In addition, miR-29b sensitizes multiple myeloma cells to bortezomib-induced apoptosis through the activation of a feedback loop with the transcription factor Sp1 (Amodio et al, 2012a).…”

Section: The Regulation Of Mir-29bmentioning

confidence: 97%