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Phone: (404) 752-1581
Fax: (404) 752-1179
Dr. Gonzalez’s laboratory is intensively investigating the specific signaling mechanisms involved in the leptin actions in cancer. To this end, his laboratory is using several molecular biology and cell signaling approaches and performing in vivo studies in mice. The protein leptin, although mainly secreted by the fat tissue and primarily known for its roles in obesity, reproductive function and embryo implantation, is considered to be responsible for the long recognized causal link between obesity and the increased risk of cancer. Leptin, a pleiotropic cytokine, is mainly secreted by adipose tissue but also overexpressed by cancer cells where it induces the expression of angiogenic, proliferative and anti-apoptotic factors. Strikingly, leptin/leptin receptor (OB-R) and VEGF/VEGFR-2 overexpression in cancer is strongly linked to rapid growth of tumors and worse prognosis. Leptin/OB-R binding activates several canonical (JAK2/STAT; MAPK/ERK 1/2 and PI-3K/AKT1) and non-canonical signaling pathways (PKC, JNK and p38 MAP kinases) to exert an increasing number of biological effects in diverse cells. In addition, leptin activates AMPK that stimulates fatty-acid oxidation in skeletal muscle. Importantly, leptin signaling upregulates the expression of several molecules involved in proliferation, survival, inflammation and angiogenesis, i.e., c-Myc, cdk2, cyclin D1, BCL2 and surviving, b3 integrin, LIF/LIF-R and IL-1 system. Dr. Gonzalez’s lab has also found that leptin induces Notch signaling. Notch plays an important role in an enormous diversity of developmental processes and its dysfunction is implicated in many cancers. Therefore, Dr. Gonzalez’s lab is investigating how specific cross-talk between leptin, IL-1 and Notch signaling impacts on tumor growth and angiogenesis. To investigate how leptin regulates tumor angiogenesis the 5’-end transcription region of VEGF, VEGFR-2 and IL-1 genes were cloned and used to establish reporter-Luc assays in cancer cells using both genetic and pharmacologic approaches. Leptin upregulates VEGF via canonical and non-canonical signaling pathways and NFkB/HIF-1a. VEGFR-2 transcription and expression is heavily depending on leptin-Notch crosstalk and, gene methylation and histone acetylation that could be linked to leptin’s effects. IL-1 system is upregulated by leptin through multiple signaling pathways that activate NFkB and SP transcription factors. Dr. Gonzalez has developed novel antagonists of leptin signaling (i.e., leptin receptor antagonists or LPrAs). High molecular derivatives of LPrAs (PEG-LPrA) with extended half-life are effective inhibitors of leptin signaling in a variety of cancers. LPrAs negatively impacted the growth of mouse tumors derived from 4T1 cells in BALB/c syngeneic, DMBA (a carcinogenic) in C57BL/J6 mice and human ER+ or ER- xenografts in SCID mice. LPrA also significantly reduced angiogenesis, proliferation, inflammation-related factors (VEGF/VEGFR-2, cyclin D1, PCNA, PECAM, leptin/OB-R, and the CD68+ cells) compared to untreated or scrambled peptides-treated controls. LPrA treatment could be an innovative adjuvant for prevention/treatment of breast and other cancer types. Dr. Gonzalez’s investigations are equally important for many processes where leptin plays a role, i.e., fertility regulation, endometriosis, arthritis, diabetes, etc.
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