A novel functional interplay between Progesterone Receptor‐B and <scp>PTEN</scp>, <i>via</i> <scp>AKT</scp>, modulates autophagy in breast cancer cells

Amicis, Francesca De; Guido, Carmela; Santoro, Marta; Lanzino, Marilena; Panza, Salvatore; Avena, Paola; Panno, Maria Luisa; Perrotta, Ida; Aquila, Saveria; Andò, Sebastiano

doi:10.1111/jcmm.12363

Cited by 35 publications

(31 citation statements)

References 48 publications

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“…Progesterone receptors action in mediating progesterone effects is highly context dependent and heavily influenced by post-translational modifications [ 4 ] as well as cofactor availability [ 5 ]. Several independent in vitro studies have demonstrated the inhibitory action of progesterone on breast cancer cell growth [ 6 – 8 ] and in agreement with these findings in a very recent paper we report that hydroxyprogesterone (OHPg), via PR-B isoform, leads to a reduced cell survival due to autophagy induction [ 9 ] through PTEN up-regulation.…”

Section: Introductionsupporting

confidence: 89%

“…Beclin-1 is a component of the class IIIPI3 kinase complex which is required for autophagy activation by various stimuli [ 23 , 24 ]. Stemming from our data indicating that 10 nM OHPg via PR-B [ 9 ] increases protein and mRNA levels of Beclin-1 in T47-D and MCF-7 cells (Figure 1A-1C ), we next investigated the effects of OHPg/PR-B on Beclin-1 gene transcription. To this aim we performed transient transfection studies by using the 5′ flanking region of Beclin-1 expression vector and two different deleted constructs (Figure 2A , left panel ) [ 23 ].…”

Section: Resultsmentioning

confidence: 99%

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Ligand activated progesterone receptor B drives autophagy-senescence transition through a Beclin-1/Bcl-2 dependent mechanism in human breast cancer cells

et al. 2016

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Loss of progesterone-receptors (PR) expression is associated with breast cancer progression. Herein we provide evidence that OHPg/PR-B through Beclin-1 evoke autophagy-senescence transition, in breast cancer cells. Specifically, OHPg increases Beclin-1 expression through a transcriptional mechanism due to the occupancy of Beclin-1 promoter by PR-B, together with the transcriptional coactivator SRC-2. This complex binds at a canonical half progesterone responsive element, which is fundamental for OHPg effects, as shown by site-directed mutagenesis. Beside, OHPg via non-genomic action rapidly activates JNK, which phosphorylates Bcl-2, producing the functional release from Beclin-1 interaction. This is not linked to an efficient autophagic flux, since p62 levels, marker of degradation via lysosomes, were not reduced after sustained OHPg stimulus. Instead, the cell cycle inhibitor p27 was induced, together with an irreversible G1 arrest, hallmark of cellular senescence. Specifically the increase of senescence-associated β-galactosidase activity was blocked by Bcl-2 siRNA but also by Beclin-1 siRNA. Collectively these findings support the importance of PR-B expression in breast cancer cells, thus targeting PR-B may be a useful strategy to provide additional approaches to existing therapies for breast cancer patients.

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Section: Introductionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Ligand activated progesterone receptor B drives autophagy-senescence transition through a Beclin-1/Bcl-2 dependent mechanism in human breast cancer cells

et al. 2016

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“…The PI3K/Akt/mTOR signaling pathway has been reported to be an important negative regulator of autophagy ( Heras-Sandoval et al, 2014 ). PTEN can regulate autophagy in mammalian cells by antagonizing PI3K through its lipid phosphatase activity ( De Amicis et al, 2014 ). Moreover, PTEN can also affect the brain development as suggested by its abundant expression in embryonic central nervous system ( Gimm et al, 2000 ).…”

Section: Discussionmentioning

confidence: 99%

Activation of Autophagy Contributes to Sevoflurane-Induced Neurotoxicity in Fetal Rats

Zhang

et al. 2017

Front. Mol. Neurosci.

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Numerous animal studies have demonstrated that commonly used general anesthetics may result in cognitive impairment in the immature brain. The prevailing theory is that general anesthetics could induce developmental neurotoxicity via enhanced apoptosis. In addition, inhibited proliferation induced by anesthetics has also been reported. So far, whether autophagy, a well-conserved cellular process that is critical for cell fate, also participates in anesthesia-induced neurotoxicity remains elusive. Here, we first examined autophagy-related changes after sevoflurane exposure and the effect of autophagy on apoptosis and proliferation, and we also explored the underlying mechanisms of autophagy activation. Pregnant rats were exposed to 2 or 3.5% sevoflurane for 2 h on gestational day 14 (G14); then, markers of autophagy and expression of autophagy pathway components were measured in fetal brains 2, 12, 24, and 48 h after anesthesia. Changes in neural stem cell (NSC) apoptosis, neurogenesis, neuron quantity and learning and memory function were examined after administration of an autophagy or PTEN inhibitor. The expression of microtubule-associated protein 1 light chain 3 (LC3)-II, Beclin-1 and phosphatase and tensin homolog on chromosome 10 (PTEN) were increased in the 3.5% sevoflurane group, while Sequestosome 1 (P62/SQSTM1), phospho-protein kinase B/protein kinase B (p-Akt/Akt) and mammalian target of rapamycin (mTOR) were decreased. 3-methyladenine (3-MA), an inhibitor of autophagy, or dipotassium bisperoxo-(5-hydroxypyridine-2-carboxyl)-oxovanadate (V) (bpV), a PTEN inhibitor, significantly attenuated the activation of autophagy, reversed the decreased expression of B-cell lymphoma-2 (Bcl-2) and reduced the number of terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) positive cells, ameliorated the decline of Nestin expression, Ki67 positive cell rate, neuron quantity and cross platform times, and shortened the prolonged escape latency. Our results demonstrated that 2 h 3.5% sevoflurane exposure at G14 induced excessive autophagy in the fetal brain via the PTEN/Akt/mTOR pathway. Autophagy inhibition reversed anesthesia-induced NSC apoptosis, proliferation decline and memory deficits.

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“…Moreover, the TransAttack study showed that the lowest PgR percentage quartile had an unfavourable prognosis as compared to the highest quartile [ 50 ]. A proposed mechanism is that ligand activation of PgR induces PTEN expression and thereby inhibits the PI3K/AKT pathway [ 51 ]. In addition, PgR associates with ERα resulting in an increased anti-proliferative effect by a unique gene expression program that is associated with good clinical outcome.…”

Section: Discussionmentioning

confidence: 99%

Lipoprotein subfractions by nuclear magnetic resonance are associated with tumor characteristics in breast cancer

et al. 2016

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BackgroundHigh-Density Lipoprotein (HDL)-cholesterol, has been associated with breast cancer development, but the association is under debate, and whether lipoprotein subfractions is associated with breast tumor characteristics remains unclear.MethodsAmong 56 women with newly diagnosed invasive breast cancer stage I/II, aged 35–75 years, pre-surgery overnight fasting serum concentrations of lipids were assessed, and body mass index (BMI) was measured. All breast tumors were immunohistochemically examined in the surgical specimen. Serum metabolomics of lipoprotein subfractions and their contents of cholesterol, free cholesterol, phospholipids, apolipoprotein-A1 and apolipoprotein-A2, were assessed using nuclear magnetic resonance. Principal component analysis, partial least square analysis, and uni- and multivariable linear regression models were used to study whether lipoprotein subfractions were associated with breast cancer tumor characteristics.ResultsThe breast cancer patients had following means: age at diagnosis: 55.1 years; BMI: 25.1 kg/m2; total-Cholesterol: 5.74 mmol/L; HDL-Cholesterol: 1.78 mmol/L; Low-Density Lipoprotein (LDL)-Cholesterol: 3.45 mmol/L; triglycerides: 1.18 mmol/L. The mean tumor size was 16.4 mm, and the mean Ki67 hotspot index was 26.5 %. Most (93 %) of the patients had estrogen receptor (ER) positive tumors (≥1 % ER+), and 82 % had progesterone receptor (PgR) positive tumors (≥10 % PgR+). Several HDL subfraction contents were strongly associated with PgR expression: Apolipoprotein-A1 (β 0.46, CI 0.22–0.69, p < 0.001), HDL cholesterol (β 0.95, CI 0.51–1.39, p < 0.001), HDL free cholesterol (β 2.88, CI 1.28–4.48, p = 0.001), HDL phospholipids (β 0.70, CI 0.36–1.04, p < 0.001). Similar results were observed for the subfractions of HDL1-3. We observed inverse associations between HDL phospholipids and Ki67 (β -0.25, p = 0.008), and in particular between HDL1’s contents of cholesterol, phospholipids, apolipoprotein-A1, apolipoprotein-A2 and Ki67. No association was observed between lipoproteins and ER expression.ConclusionOur findings hypothesize associations between different lipoprotein subfractions, and PgR expression, and Ki 67 % in breast tumors. These findings may have clinical implications, but require confirmation in larger studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-016-0225-4) contains supplementary material, which is available to authorized users.

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A novel functional interplay between Progesterone Receptor‐B and PTEN, via AKT, modulates autophagy in breast cancer cells

Cited by 35 publications

References 48 publications

Ligand activated progesterone receptor B drives autophagy-senescence transition through a Beclin-1/Bcl-2 dependent mechanism in human breast cancer cells

Ligand activated progesterone receptor B drives autophagy-senescence transition through a Beclin-1/Bcl-2 dependent mechanism in human breast cancer cells

Activation of Autophagy Contributes to Sevoflurane-Induced Neurotoxicity in Fetal Rats

Lipoprotein subfractions by nuclear magnetic resonance are associated with tumor characteristics in breast cancer

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