Role of mitochondria and cardiolipins in growth inhibition of breast cancer cells by retinoic acid

Terao, Mineko; Goracci, Laura; Celestini, Valentina; Kurosaki, Mami; Bolis, Marco; Veroli, Alessandra Di; Vallerga, Arianna; Fratelli, Maddalena; Lupi, Monica; Corbelli, Alessandro; Fiordaliso, Fabio; Giannı̀, Maurizio; Paroni, Gabriela; Zanetti, Adriana; Cruciani, Gabriele; Garattini, Enrico

doi:10.1186/s13046-019-1438-y

Cited by 13 publications

(11 citation statements)

References 60 publications

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“…NB4 and NB4.306 cells were exposed to vehicle (DMSO) or ATRA (1 μM) for 6, 24, and 48 h, three time-points preceding the retinoid-dependent differentiation of NB4 cells into granulocytes which starts to be evident following 72–96 h [ 9 ]. Using a lipidomic approach [ 18 ], we determined the number and types of lipids observed in the two cell-lines. Principal-component-analysis (PCA) indicates that NB4 and NB4.306 cells present with similar lipidomic profiles under basal conditions and the perturbations induced by ATRA are limited (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

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Role of cardiolipins, mitochondria, and autophagy in the differentiation process activated by all-trans retinoic acid in acute promyelocytic leukemia

et al. 2022

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The role played by lipids in the process of granulocytic differentiation activated by all-trans retinoic acid (ATRA) in Acute-Promyelocytic-Leukemia (APL) blasts is unknown. The process of granulocytic differentiation activated by ATRA in APL blasts is recapitulated in the NB4 cell-line, which is characterized by expression of the pathogenic PML-RARα fusion protein. In the present study, we used the NB4 model to define the effects exerted by ATRA on lipid homeostasis. Using a high-throughput lipidomic approach, we demonstrate that exposure of the APL-derived NB4 cell-line to ATRA causes an early reduction in the amounts of cardiolipins, a major lipid component of the mitochondrial membranes. The decrease in the levels of cardiolipins results in a concomitant inhibition of mitochondrial activity. These ATRA-dependent effects are causally involved in the granulocytic maturation process. In fact, the ATRA-induced decrease of cardiolipins and the concomitant dysfunction of mitochondria precede the differentiation of retinoid-sensitive NB4 cells and the two phenomena are not observed in the retinoid-resistant NB4.306 counterparts. In addition, ethanolamine induced rescue of the mitochondrial dysfunction activated by cardiolipin deficiency inhibits ATRA-dependent granulocytic differentiation and induction of the associated autophagic process. The RNA-seq studies performed in parental NB4 cells and a NB4-derived cell population, characterized by silencing of the autophagy mediator, ATG5, provide insights into the mechanisms underlying the differentiating action of ATRA. The results indicate that ATRA causes a significant down-regulation of CRLS1 (Cardiolipin-synthase-1) and LPCAT1 (Lysophosphatidylcholine-Acyltransferase-1) mRNAs which code for two enzymes catalyzing the last steps of cardiolipin synthesis. ATRA-dependent down-regulation of CRLS1 and LPCAT1 mRNAs is functionally relevant, as it is accompanied by a significant decrease in the amounts of the corresponding proteins. Furthermore, the decrease in CRLS1 and LPCAT1 levels requires activation of the autophagic process, as down-regulation of the two proteins is blocked in ATG5-silenced NB4-shATG5 cells.

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Section: Resultsmentioning

confidence: 99%

“…We focussed on CLs , as these lipids are reduced by ATRA also in breast-cancer cell-lines [ 18 ]. CLs localize to mitochondrial membranes and are involved in the bio-energetic processes [ 20 , 21 ].…”

Section: Resultsmentioning

confidence: 99%

Role of cardiolipins, mitochondria, and autophagy in the differentiation process activated by all-trans retinoic acid in acute promyelocytic leukemia

et al. 2022

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“…This suggests that down-regulation of the MYC-pathway contributes to the anti-proliferative action of the two compounds. Furthermore, both ATRA and DAPT reduce oxidative phosphorylation, which is consistent with a growth-inhibitory action involving a decrease in mitochondrial activity [ 36 ]. As for the up-regulated pathways, ATRA causes a significant enrichment of the “ Interferon-alpha-response ” and “ Interferon-gamma-response ” gene sets [ 19 ].…”

Section: Resultsmentioning

confidence: 66%

Retinoic Acid Sensitivity of Triple-Negative Breast Cancer Cells Characterized by Constitutive Activation of the notch1 Pathway: The Role of Rarβ

Paroni

Zanetti

Barzago

et al. 2020

Cancers

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Triple-negative breast cancer (TNBC) is a heterogeneous disease that lacks effective therapeutic options. In this study, we profile eighteen TNBC cell lines for their sensitivity to the anti-proliferative action of all-trans retinoic acid (ATRA). The only three cell lines (HCC-1599, MB-157 and MDA-MB-157) endowed with ATRA-sensitivity are characterized by genetic aberrations of the NOTCH1-gene, causing constitutive activation of the NOTCH1 γ-secretase product, N1ICD. N1ICD renders HCC-1599, MB-157 and MDA-MB-157 cells sensitive not only to ATRA, but also to γ-secretase inhibitors (DAPT; PF-03084014). Combinations of ATRA and γ-secretase inhibitors produce additive/synergistic effects in vitro and in vivo. RNA-sequencing studies of HCC-1599 and MB-157 cells exposed to ATRA and DAPT and ATRA+DAPT demonstrate that the two compounds act on common gene sets, some of which belong to the NOTCH1 pathway. ATRA inhibits the growth of HCC-1599, MB-157 and MDA-MB-157 cells via RARα, which up-regulates several retinoid target-genes, including RARβ. RARβ is a key determinant of ATRA anti-proliferative activity, as its silencing suppresses the effects exerted by the retinoid. In conclusion, we demonstrate that ATRA exerts a significant anti-tumor action only in TNBC cells showing constitutive NOTCH1 activation. Our results support the design of clinical trials involving combinations between ATRA and γ-secretase inhibitors for the treatment of this TNBC subtype.

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“…This suggests that down-regulation of the MYC-pathway contributes to the anti-proliferative action of the two compounds. Furthermore, both ATRA and DAPT reduce oxidative-phosphorylation, consistent with a growth-inhibitory action involving a decrease in mitochondrial activity (34). As for the up-regulated pathways, ATRA causes a signi cant enrichment of the "Interferon-alpha-response" and "Interferon-gamma-response" gene-networks (18).…”

Section: Transcriptomic Perturbations Afforded By Atra and Dapt Alonementioning

confidence: 74%

Retinoic Acid Sensitivity of Triple-Negative Breast-Cancer Cells Characterized by Constitutive Activation of the NOTCH1 Pathway: The Role of RARβ

Paroni

Zanetti

Barzago

et al. 2020

Preprint

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Background: All-trans retinoic-acid (ATRA) is a promising agent in the personalized treatment/chemo-prevention of breast-cancer. Triple-negative breast-cancer (TNBC) accounts for 15-20% of all mammary tumours and share common features such as a high proliferation index and a basal-like gene expression signature. In spite of this, TNBC is very heterogeneous and lacks effective therapeutic strategies.Methods: We profile eighteen TNBC breast-cancer cell-lines for their sensitivity to the anti-proliferative action of ATRA. In addition, we perform RNA-sequencing studies in two of the most sensitive cell-lines exposed to ATRA, a γ-secretase inhibitor and combinations thereof. Results: The only three TNBC cell-lines (HCC-1599, MB-157 and MDA-MB-157) endowed with ATRA-sensitivity are characterized by constitutive activation of the NOTCH1 γ-secretase product, N1ICD and we identify the associated genetic aberrations of the NOTCH1-gene. N1ICD expression renders HCC-1599, MB-157 and MDA-MB-157 cells sensitive not only to ATRA, but also to γ-secretase inhibitors, like DAPT [N-(N-(3,5-difluorophenacetyl)-L-alanyl)-S-phenylglycine-t-butyl-ester] and PF-03084014. The anti-proliferative action of ATRA and γ-secretase inhibitors is complementary, as combinations of ATRA and DAPT or PF-03084014 cause synergistic effects. This synergism is confirmed in mouse xenografts of HCC-1599 cells. RNA-sequencing studies performed in HCC-1599 and MB-157 cells exposed to ATRA and DAPT demonstrate that the two compounds act on common gene-sets, some of which belong to the NOTCH1 pathway. ATRA inhibits the growth of HCC-1599, MB-157 and MDA-MB-157 cells via RARα, which up-regulates several retinoid target-genes, including RARβ. RARβ induction is observed only in HCC-1599, MB-157 and MDA-MB-157 cells, as the other TNBC cell-lines lack ATRA-dependent stimulation of the retinoid-receptor. RARβ is a key determinant of ATRA anti-proliferative activity, as its silencing suppresses the effects exerted by the retinoid. Conclusions: We demonstrate that ATRA exerts a significant anti-tumor action in TNBC cells characterized by constitutive NOTCH1 activation. We show that ATRA enhances the anti-tumor activity of γ-secretase inhibitors in an additive/synergistic manner. We support the idea that ATRA anti-proliferative activity is mediated by the Retinoid-Acid-Receptor-β (RARβ). The present study represents the basis for the design of clinical trials on the efficacy of combinations between ATRA and γ-secretase inhibitors in the treatment of patients affected by a specific subtype of TNBC.

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Role of mitochondria and cardiolipins in growth inhibition of breast cancer cells by retinoic acid

Cited by 13 publications

References 60 publications

Role of cardiolipins, mitochondria, and autophagy in the differentiation process activated by all-trans retinoic acid in acute promyelocytic leukemia

Role of cardiolipins, mitochondria, and autophagy in the differentiation process activated by all-trans retinoic acid in acute promyelocytic leukemia

Retinoic Acid Sensitivity of Triple-Negative Breast Cancer Cells Characterized by Constitutive Activation of the notch1 Pathway: The Role of Rarβ

Retinoic Acid Sensitivity of Triple-Negative Breast-Cancer Cells Characterized by Constitutive Activation of the NOTCH1 Pathway: The Role of RARβ

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