Peroxisome Proliferator Activated Receptor-α/Hypoxia Inducible Factor-1α Interplay Sustains Carbonic Anhydrase IX and Apoliprotein E Expression in Breast Cancer Stem Cells

Papi, Alessio; Storci, Gianluca; Guarnieri, Tiziana; Carolis, Sabrina De; Bertoni, Sara; Avenia, Nicola; Sanguinetti, Alessandro; Sidoni, Angelo; Santini, Donatella; Ceccarelli, Claudio; Taffurelli, Mario; Orlandi, Marina; Bonafè, Massimiliano

doi:10.1371/journal.pone.0054968

Cited by 36 publications

(50 citation statements)

References 58 publications

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“…However, our results indicate that this gene mRNA expression could be reversed by MK886 treatment. The ability of MK886 to decrease the expression of VEGF has been previously reported in a study on human pancreatic cancer cells (Zhou et al 2011), whereas a recent study conducted by Papi et al (2013) showed that PPARa and HIF1a have functional interplays in which their expressions are enhanced by each other, resulting in pro-inflammatory responses. This would support the current finding that HIF1a positively correlates with the expression of PPARa.…”

Section: Discussionmentioning

confidence: 72%

MK886 inhibits the pioglitazone-induced anti-invasion of MDA-MB-231 cells is associated with PPARα/γ, FGF4 and 5LOX

2016

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The goal of this study was to determine the effects of PGZ and MK886 on the mRNA expression of PPARa and other associated genes in MDA-MB-231 cells, and the biological mechanisms induced by both drugs were also assessed. The levels of PPARa mRNA expression in PGZ-treated and MK886-treated MDA-MB-231 cells were determined using real-time PCR; the growth inhibitory effects of PGZ and MK886 were determined using the trypan blue exclusion assay; the induction of apoptosis by PGZ and MK886 was determined using DNA fragmentation assay and real-time PCR; and the invasion of PGZ-treated and MK886-treated MDA-MB-231 cells was determined using the wound healing and transwell migration assays. In addition, we correlated the expression of PPARa mRNA with other genes, including PPARc, FGF4 and 5LOX, in drug-treated MDA-MB-231 cells. Our results demonstrated that the treatment of MDA-MB-231 cells with PGZ increased the expression of PPARa/c mRNA and that this expression could be inhibited by treatment with MK886. Both drugs reduced the viability of MDA-MB-231 cells independently of PPARa/c mRNA expression but did not induce apoptosis. The wound caused by invasion was not healed by PGZ-treated MDA-MB-231 cells, but it was healed by MK886-treated cancer cells, indicating that the reduction of invasion in PGZ-treated MDA-MB-231 cells was eliminated by treatment with MK886, and this finding was validated by the transwell migration assay. This phenomenon might also be associated with the expression of PPARa/c, FGF4 and 5LOX mRNA in the treated cancer cells. This study provides useful information regarding the mRNA expression levels of PPARa and other related genes in MDA-MB-231 cells. These genes could be attractive targets for reducing the invasion of breast cancer.

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Section: Discussionmentioning

confidence: 72%

MK886 inhibits the pioglitazone-induced anti-invasion of MDA-MB-231 cells is associated with PPARα/γ, FGF4 and 5LOX

2016

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“…It has been proposed that "NF-kB activity addiction" would make CSCs more susceptible to NF-kB inhibitors than their normal counterparts [26,55] . For these reasons the use of molecules, as NRs ligands, capable of inhibiting NF-kB dependent inflammation may be the best strategy to hamper BCSCs growth [74,86] . Recently, we demonstrated that BCSCs have a particular NRs phenotype [86,87] (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

“…For these reasons the use of molecules, as NRs ligands, capable of inhibiting NF-kB dependent inflammation may be the best strategy to hamper BCSCs growth [74,86] . Recently, we demonstrated that BCSCs have a particular NRs phenotype [86,87] (Figure 1). Therefore, the synergic use of multiple molecules (as ligands of NRs) at lower doses might be a good strategy to kill BCSCs, while inducing fewer side effects in patients.…”

Section: Resultsmentioning

confidence: 99%

“…More recently it has been seen that WY-14643 promotes the formation of a MS-tumour (derived from cells of the mammary tumour cell line MCF-7) by stimulating the activation of the NF-kB/IL-6 and, consequently, the expression of genes Slug, Notch-3, Jagged-1, whereas the silencing of PPARα with a specific siRNA reduces tumour-MS formation. Furthermore, PPARα expression is positively correlated with the phenotype of BCSCs obtained from specimens of breast cancer patients [86] . Finally, we have recently demonstrated that IIF potentiates the ability of PGZ to hamper the MS-forming capability of human breast tumours and MCF7 cancer cells, reducing the expression of CSCs regulatory genes (Notch3, Jagged1, SLUG, IL-6, Apolipoprotein E, HIF-1α and CAIX).…”

Section: Ppar Receptors and Their Agonistsmentioning

confidence: 98%

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Role of nuclear receptors in breast cancer stem cells

Papi

Orlandi

2016

WJSC

Self Cite

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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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“…They found that p66Shc/Notch-3 interplay modulates self-renewal (by inducing Notch-ligand Jagged-1) and hypoxia survival (by inducing CA9) in mammary gland stem/progenitor cells (Sansone et al 2007a, b). They also recently demonstrated that the peroxisome proliferator-activated receptor-α/hypoxia inducible factor-1α (PPAR-α/HIF-1α) interplay induces the expression of CA9 along with interleukin-6 (IL-6) and apolipoprotein E (Papi et al 2013). …”

Section: Transcriptional Regulation Of the Ca9 Genementioning

confidence: 99%

Carbonic Anhydrase IX: From Biology to Therapy

Pastoreková¹,

Supuran²

2013

Hypoxia and Cancer

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Growing tumor tissues develop a stressful microenvironment characterized by hypoxia and acidosis. Tumor cells can survive these stresses via induction of adaptive transcriptional changes mediated primarily by the hypoxia-inducible factor (HIF), and via stimulation of ion transport machinery maintaining normal intracellular pH. In addition, through these adaptive responses tumor cells acquire new features endowing them with selective advantage in migration, invasion, metastasis, and resistance to therapy. Carbonic anhydrase IX (CA IX), a highly active cancer-related carbonic anhydrase isoform, is linked to both hypoxia, as a direct transcriptional target of HIF, and acidosis, as a component of mechanisms that facilitate ion transport across the plasma membrane and thereby counteract the intracellular accumulation of acidic metabolic products. Expression pattern of CA IX in human tumors reflects the activation of the HIF pathway by physiologic hypoxia, genetic defects, and/or oncogenic events. Moreover, CA IX plays an active role not only in pH regulation but also in cell migration and invasion. Thus, it is often exploited and/or investigated as an intrinsic marker of hypoxia, a prognostic indicator, and a therapeutic target for antibodies or inhibitors of the enzyme activity. It is believed that these CA IXtargeted therapeutic approaches can mediate the selective killing of CA IX-positive cells or sensitize tumor cells to conventional treatment modalities. In addition, both

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Peroxisome Proliferator Activated Receptor-α/Hypoxia Inducible Factor-1α Interplay Sustains Carbonic Anhydrase IX and Apoliprotein E Expression in Breast Cancer Stem Cells

Cited by 36 publications

References 58 publications

MK886 inhibits the pioglitazone-induced anti-invasion of MDA-MB-231 cells is associated with PPARα/γ, FGF4 and 5LOX

MK886 inhibits the pioglitazone-induced anti-invasion of MDA-MB-231 cells is associated with PPARα/γ, FGF4 and 5LOX

Role of nuclear receptors in breast cancer stem cells

Carbonic Anhydrase IX: From Biology to Therapy

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