ABLATING LEPTIN-MEDIATED CELL SURVIVAL WITH SMALL LEPTIN ANTAGONIST IN VARIOUS CANCERS
The risk for cancer development and progression continues to be linked to obesity via excessive circulating levels of the adipokine leptin, which is primarily secreted from white adipose tissue. In the context of cancer, circulating leptin binds to its receptor (OB-R), which has been shown to be overexpressed by cancer cells, leading to aberrant leptin/OB-R signaling. Activation of leptin signaling pathways in cancer cells is associated with S-phase progression, angiogenesis, apoptosis evasion, and cell invasion and migration. Therefore, blocking leptin signaling in highly aggressive cancers that lack specific treatment could be a novel therapeutic strategy. Our aim was to investigate the efficacy of leptin antagonism in abrogating the deleterious effects leptin signaling in triple negative breast cancer. To this end, we tested the hypothesis that leptin antagonists will prevent leptin-induced activation of proliferation and cell cycle progression in triple negative breast cancer cells (MDA-MB 231 and MDA-MB 468). Data generated show that the antagonists effectively blocked p-STAT3 and cyclin D induced by leptin in cancer cells. Leptin antagonism was shown to increase the effects of chemotherapeutic drugs. Additionally, the antagonists did not exert toxic effects in non-malignant cells (MCF-10A cell line). Leptin-mediated progression of S-phase was also reduced by the antagonists, which correlated with the abrogation of leptin-induced proliferation of breast cancer cells. PCR analysis demonstrated that blockade of leptin signaling decreased SOX3 gene expression (a transcription factor linked to proliferative and oncogenic signature). Taken together these data suggest that leptin signaling may be a therapeutic target in combating obesity-related chemotherapeutic resistance.
YHC Undergraduate Research fund
Lipsey*, Crystal C.; Huff, Lyn; Robey, Rob; Gottesman, Michael M.; and Gonzalez-Perez, Ruben R.
"ABLATING LEPTIN-MEDIATED CELL SURVIVAL WITH SMALL LEPTIN ANTAGONIST IN VARIOUS CANCERS,"
Georgia Journal of Science, Vol. 77, No. 1, Article 1.
Available at: https://digitalcommons.gaacademy.org/gjs/vol77/iss1/1