INHIBITING CELL SURVIVAL OF OBESITY-RELATED CANCER WITH LEPTIN ANTAGONISTS
Obesity is a comorbidity in many aggressive diseases and has been identify as a risk factor for at least 13 different types of cancers. Adverse outcomes associated with obesity-related cancer progression have been demonstrated previously in both breast and pancreatic cancer. The mechanisms regulating obesity-related cancer outcomes are still unclear; however, it has been demonstrated that leptin signaling induces survival of human cancer cells in vitro and in vivo. Leptin is a 16kD cytokine that is secreted from adipocytes and normally functions to control satiety and energy balance. Clinical studies indicate that circulating leptin levels increase in proportion to an individual’s body fat. Literature also shows that several types of cancer cells overexpress the leptin receptor (OB-R). Leptin signaling pathways can lead to increased proliferation and survival of cancer cells. Leptin/OB-R binding initiates Stat3 phosphorylation by recruitment of JAK2 kinase to the intracytoplasmatic tail of OB-R. Phosphorylated Stat3 forms dimers that trigger the expression several genes involved in cell cycle activation and progression. Our laboratory previously demonstrated a link between leptin-induced S-phase progression of the cell cycle, angiogenesis, apoptosis evasion, and cell invasion and migration in highly aggressive breast and pancreatic cancer cell lines. Consequently, our group has developed several novel leptin antagonists as inhibitors of obesity-related cancer cell survival. Our current study demonstrates that antagonists are non-toxic in non-malignant breast cells. Furthermore, the results show a significant reduction of pStat3 levels and other molecules in triple negative breast and pancreatic cancer cells treated with leptin. It is envisaged that blocking leptin signaling could be a new strategy to treat obesity-related cancers.
Lipsey*, Crystal C.; Harbuzariu, Adriana; and Gonzalez-Perez, Ruben R.
"INHIBITING CELL SURVIVAL OF OBESITY-RELATED CANCER WITH LEPTIN ANTAGONISTS,"
Georgia Journal of Science, Vol. 76, No. 1, Article 55.
Available at: https://digitalcommons.gaacademy.org/gjs/vol76/iss1/55