Leptin Receptor as a Potential Target to Inhibit Human Testicular Seminoma Growth

Panza, Salvatore; Gelsomino, Luca; Malivindi, Rocco; Rago, Vittoria; Barone, Ines; Giordano, Cinzia; Giordano, Francesca; Leggio, Antonella; Comandè, Alessandra; Liguori, Angelo; Aquila, Saveria; Bonofiglio, Daniela; Andò, Sebastiano; Catalano, Stefania

doi:10.1016/j.ajpath.2018.11.012

Cited by 14 publications

(15 citation statements)

References 55 publications

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“…Moreover, leptin exposure increased cell migration in both wound healing ( Figure 2 b) and transmigration ( Figure 2 c) assays, suggesting that this cytokine could facilitate the invasive behavior of GBM cells. The direct involvement of leptin/leptin receptor-mediated signaling in the observed effects was confirmed by using a selective leptin receptor antagonist, the peptide LDFI, a small peptide of the wild-type sequence of the leptin binding site I (Leu-Asp-Phe-Ile), synthesized by solid phase methodologies, which we previously demonstrated to specifically inhibit both the in vitro and in vivo leptin signaling pathway [ 8 , 37 , 42 , 43 ].…”

Section: Resultsmentioning

confidence: 99%

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Leptin and Notch Signaling Cooperate in Sustaining Glioblastoma Multiforme Progression

et al. 2020

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Glioblastoma multiforme (GBM) is the most malignant form of glioma, which represents one of the commonly occurring tumors of the central nervous system. Despite the continuous development of new clinical therapies against this malignancy, it still remains a deadly disease with very poor prognosis. Here, we demonstrated the existence of a biologically active interaction between leptin and Notch signaling pathways that sustains GBM development and progression. We found that the expression of leptin and its receptors was significantly higher in human glioblastoma cells, U-87 MG and T98G, than in a normal human glial cell line, SVG p12, and that activation of leptin signaling induced growth and motility in GBM cells. Interestingly, flow cytometry and real-time RT-PCR assays revealed that GBM cells, grown as neurospheres, displayed stem cell-like properties (CD133+) along with an enhanced expression of leptin receptors. Leptin treatment significantly increased the neurosphere forming efficiency, self-renewal capacity, and mRNA expression levels of the stemness markers CD133, Nestin, SOX2, and GFAP. Mechanistically, we evidenced a leptin-mediated upregulation of Notch 1 receptor and the activation of its downstream effectors and target molecules. Leptin-induced effects on U-87 MG and T98G cells were abrogated by the selective leptin antagonist, the peptide LDFI (Leu-Asp-Phe-Ile), as well as by the specific Notch signaling inhibitor, GSI (Gamma Secretase Inhibitor) and in the presence of a dominant-negative of mastermind-like-1. Overall, these findings demonstrate, for the first time, a functional interaction between leptin and Notch signaling in GBM, highlighting leptin/Notch crosstalk as a potential novel therapeutic target for GBM treatment.

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Section: Resultsmentioning

confidence: 99%

“…U-87 MG and T98G cells were treated as described for 24 h. For the last 6 h, [ 3 H]Thymidine (1μCi/mL) was added to the culture medium, After incubation, cells were processed as previously described [ 37 ].…”

Section: Methodsmentioning

confidence: 99%

Leptin and Notch Signaling Cooperate in Sustaining Glioblastoma Multiforme Progression

et al. 2020

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“…Images represent one of three independent experiments (10× magnification) (OLIMPUS-BX51 microscope). The rate of wound-healing was quantified, as described in [45].…”

Section: Wound-healing Assaysmentioning

confidence: 99%

Leptin Signaling Contributes to Aromatase Inhibitor Resistant Breast Cancer Cell Growth and Activation of Macrophages

et al. 2020

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Obesity represents a risk factor for breast cancer development and therapy resistance, but the molecular players underling these links are unclear. Here, we identify a role for the obesity-cytokine leptin in sustaining aromatase inhibitor (AI) resistant growth and progression in breast cancer. Using as experimental models MCF-7 breast cancer cells surviving long-term treatment with the AI anastrozole (AnaR) and Ana-sensitive counterparts, we found that AnaR cells expressed higher levels of leptin and its receptors (ObR) along with a constitutive activation of downstream effectors. Accordingly, leptin signaling inhibition reduced only AnaR cell growth and motility, highlighting the existence of an autocrine loop in mechanisms governing drug-resistant phenotypes. In agreement with ObR overexpression, increasing doses of leptin were able to stimulate to a greater extent growth and migration in AnaR than sensitive cells. Moreover, leptin contributed to enhanced crosstalk between AnaR cells and macrophages within the tumor microenvironment. Indeed, AnaR, through leptin secretion, modulated macrophage profiles and increased macrophage motility through CXCR4 signaling, as evidenced by RNA-sequencing, real-time PCR, and immunoblotting. Reciprocally, activated macrophages increased AnaR cell growth and motility in coculture systems. In conclusion, acquired AI resistance is accompanied by the development of a leptin-driven phenotype, highlighting the potential clinical benefit of targeting this cytokine network in hormone-resistant breast cancers, especially in obese women.

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“…Images were acquired at 10x magnification using an OLYMPUS-BX51 microscope. The rate of wound healing was quantified as described [79].…”

Section: Wound Healing Scratch Assaysmentioning

confidence: 99%

“…All stained slides were visualized using an Olympus BX41 microscope and the images were taken with CSV1.14 software, using a CAM XC-30 for image acquisition. Immunoreactivity was evaluated by a pathologist in a blinded fashion and scored as: 0, negative; 1, weakly positive; 2, moderately positive; 3, strongly positive; and 4, very strongly positive [79].…”

Section: Immunohistochemistrymentioning

confidence: 99%

Knockdown of Leptin Receptor Affects Macrophage Phenotype in the Tumor Microenvironment Inhibiting Breast Cancer Growth and Progression

Gelsomino

Naimo

Malivindi

et al. 2020

Cancers

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Aberrant leptin (Ob) signaling, a hallmark of obesity, has been recognized to influence breast cancer (BC) biology within the tumor microenvironment (TME). Here, we evaluated the impact of leptin receptor (ObR) knockdown in affecting BC phenotype and in mediating the interaction between tumor cells and macrophages, the most abundant immune cells within the TME. The stable knockdown of ObR (ObR sh) in ERα-positive and ERα-negative BC cells turned the tumor phenotype into a less aggressive one, as evidenced by in vitro and in vivo models. In xenograft tumors and in co-culture experiments between circulating monocytes and BC cells, the absence of ObR reduced the recruitment of macrophages, and also affected their cytokine mRNA expression profile. This was associated with a decreased expression and secretion of monocyte chemoattractant protein-1 in ObR sh clones. The loss of Ob/ObR signaling modulated the immunosuppressive TME, as shown by a reduced expression of programmed death ligand 1/programmed cell death protein 1/arginase 1. In addition, we observed increased phagocytic activity of macrophages compared to control Sh clones in the presence of ObR sh-derived conditioned medium. Our findings, addressing an innovative role of ObR in modulating immune TME, may open new avenues to improve BC patient health care.

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Leptin Receptor as a Potential Target to Inhibit Human Testicular Seminoma Growth

Cited by 14 publications

References 55 publications

Leptin and Notch Signaling Cooperate in Sustaining Glioblastoma Multiforme Progression

Leptin and Notch Signaling Cooperate in Sustaining Glioblastoma Multiforme Progression

Leptin Signaling Contributes to Aromatase Inhibitor Resistant Breast Cancer Cell Growth and Activation of Macrophages

Knockdown of Leptin Receptor Affects Macrophage Phenotype in the Tumor Microenvironment Inhibiting Breast Cancer Growth and Progression

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