Leptin increases motility and integrin up‐regulation in human prostate cancer cells

Huang, Chih Yang; Yu, Hsin Shan; Lai, Tung Yuan; Yeh, Yu Lan; Su, Cheng; Hsu, His Hsien; Tsai, Fuu Jen; Tsai, Chang Hai; Wu, Hsi Chin; Tang, Chih Hsin

doi:10.1002/jcp.22455

Cited by 49 publications

(35 citation statements)

References 47 publications

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“…Similar clustering was shown by our group in myeloma, 28 but was also demonstrated for other immobilized or soluble ligands. [55][56][57][58] Pharmacologic inhibitors of the integrin blocked αv and β3 mRNA induction by T4. T3-induced αv mRNA was similarly blocked.…”

Section: Discussionmentioning

confidence: 98%

The thyroid hormone-αvβ3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation

et al. 2015

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Ovarian carcinoma is the fifth common cause of cancer death in women, despite advanced therapeutic approaches. αvβ3 integrin, a plasma membrane receptor, binds thyroid hormones (L-thyroxine, T4; 3,5,3'-triiodo-L-thyronine, T3) and is overexpressed in ovarian cancer. We have demonstrated selective binding of fluorescently labeled hormones to αvβ3-positive ovarian cancer cells but not to integrin-negative cells. Physiologically relevant T3 (1 nM) and T4 (100 nM) concentrations in OVCAR-3 (high αvβ3) and A2780 (low αvβ3) cells promoted αv and β3 transcription in association with basal integrin levels. This transcription was effectively blocked by RGD (Arg-Gly-Asp) peptide and neutralizing αvβ3 antibodies, excluding T3-induced β3 messenger RNA, suggesting subspecialization of T3 and T4 binding to the integrin receptor pocket. We have provided support for extracellular regulated kinase (ERK)-mediated transcriptional regulation of the αv monomer by T3 and of β3 monomer by both hormones and documented a rapid (30-120 min) and dose-dependent (0.1-1000 nM) ERK activation. OVCAR-3 cells and αvβ3-deficient HEK293 cells treated with αvβ3 blockers confirmed the requirement for an intact thyroid hormone-integrin interaction in ERK activation. In addition, novel data indicated that T4, but not T3, controls integrin's outside-in signaling by phosphorylating tyrosine 759 in the β3 subunit. Both hormones induced cell proliferation (cell counts), survival (Annexin-PI), viability (WST-1) and significantly reduced the expression of genes that inhibit cell cycle (p21, p16), promote mitochondrial apoptosis (Nix, PUMA) and tumor suppression (GDF-15, IGFBP-6), particularly in cells with high integrin expression. At last, we have confirmed that hypothyroid environment attenuated ovarian cancer growth using a novel experimental platform that exploited paired euthyroid and severe hypothyroid serum samples from human subjects. To conclude, our data define a critical role for thyroid hormones as potent αvβ3-ligands, driving ovarian cancer cell proliferation and suggest that disruption of this axis may present a novel treatment strategy in this aggressive disease.

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Section: Discussionmentioning

confidence: 98%

The thyroid hormone-αvβ3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation

et al. 2015

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“…It is not surprising that NF-kB has been found to be activated by leptin in many tumors, such as breast cancer [114,118], glioma [119,120], chondrosarcoma [121], prostate cancer [122] as well as CRC [82,123]. Leptin enhances migration, invasion and proliferation of malignant cells, possibly through activation of NF-kB [120,121,123].…”

Section: Nf-kb Signaling Pathwaymentioning

confidence: 99%

Oncogenic role and therapeutic target of leptin signaling in colorectal cancer

Zhou¹,

Tian

Gong

et al. 2014

Expert Opinion on Therapeutic Targets

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“…Adiponectin and leptin are abundant adipokines secreted by adipose tissue (10,11,17,26). Leptin has been the focus of a number of studies as a potential mediator of obesity-associated cancer (36,37). Leptin actions are mediated through the transmembrane leptin receptor, ObR (38)(39)(40).…”

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confidence: 99%

Analysis of circulating adipokines in patients newly diagnosed with solid cancer: Associations with measures of adiposity and tumor characteristics

et al. 2017

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Abstract. The development and progression of cancer is a complex and multifactorial process and the global prevalence of obesity is markedly increasing. A number of studies have made an association between obesity and increased rates of epithelial tumors. Obesity is associated with altered adipokine levels, potentially contributing to the process of tumor development and metastasis. In the current study, the associations between circulating adipokines and measures of adiposity and tumor characteristics among patients diagnosed with solid malignancies were examined at the time of presentation, and following the administration of chemotherapy. A total of 30 patients with cancer and matched healthy controls were enrolled in the present study. Plasma adipokine levels of hepatocyte growth factor (HGF), adiponectin and leptin were determined using commercially available ELISA kits. At baseline, plasma HGF, adiponectin and leptin levels were not significantly different between patients with cancer and the healthy controls. Circulating HGF levels were significantly associated with the stage of cancer at diagnosis (P=0.044), but lacked a significant association with lymph node status (P=0.194). Plasma adiponectin and leptin levels were not significantly associated with tumor characteristics at the time of diagnosis. Only leptin was positively correlated with the body mass index of patients with cancer (P<0.001). No significant correlations were detected between the evaluated adipokines and measures of visceral obesity, as determined by waist circumference and the waist-hip ratio at presentation. Following administration of chemotherapy, adiponectin was the only adipokine evaluated in the current study that exhibited a significant difference, when compared with baseline plasma levels (P= 0.013), and a significant positive correlation between baseline and follow-up circulating levels (P=0.002) among patients with cancer. In addition, there were no significant inter-correlations between circulating adipokines at baseline level and during follow-up in patients with cancer. Collectively, the findings of the current study suggest a lack of diagnostic roles for the adipokines investigated and no significant association with measures of adiposity. Adiponectin may be a potential adipokine to measure in patients with cancer, in order to further assess its prognostic and predictive potential. IntroductionCancer is a major public health problem and is a leading cause of mortality worldwide (1). Annual cancer cases are predicted to rise from 14 million in 2012 to 22 million within the next two decades (2). In Jordan, there has been a notable increase in the incidence and burden of cancer and, according to the most recent report from the Jordan National Cancer Registry, the number of new cancer cases diagnosed among Jordanians increased by ~46% from 2000-2012 (3). The most common types of cancer among Jordanian patients were breast, colorectal, lung, lymphoma and urinary bladder cancer (3). At present, epidemiological and experimental...

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Leptin increases motility and integrin up‐regulation in human prostate cancer cells

Cited by 49 publications

References 47 publications

The thyroid hormone-αvβ3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation

The thyroid hormone-αvβ3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation

Oncogenic role and therapeutic target of leptin signaling in colorectal cancer

Analysis of circulating adipokines in patients newly diagnosed with solid cancer: Associations with measures of adiposity and tumor characteristics

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