Metformin and JQ1 synergistically inhibit obesity-activated thyroid cancer

Compelling epidemiological evidence shows a strong positive correlation of obesity with thyroid cancer. In vivo studies have provided molecular evidence that high-fat-diet-induced obesity promotes thyroid cancer progression by aberrantly activating leptin-JAK2-STAT3 signaling in a mouse model of thyroid cancer (Thrb PV/PV Pten +/ – mice). The Thrb PV/PV Pten +/ – mouse expresses a dominantly negative thyroid hormone receptor β (denoted as PV) and a deletion of one single allele of the Pten gene. The Thrb PV/PV Pten +/ – mouse spontaneously develops follicular thyroid cancer, which allows its use as a preclinical mouse model to test potential therapeutics. We recently showed that inhibition of STAT3 activity by a specific inhibitor markedly delays thyroid cancer progression in high-fat-diet-induced obese Thrb PV/PV Pten +/ – mice (HFD-Thrb PV/PV Pten +/ – mice). Further, metformin, a widely used antidiabetic drug, blocks invasion and metastasis, but not thyroid tumor growth in HFD-Thrb PV/PV Pten +/ – mice. To improve efficacy in reducing thyroid tumor growth, we treated HFD-Thrb PV/PV Pten +/ – with JQ1, a potent inhibitor of the activity of bromodomain and extraterminal domain (BET) and with metformin. We found that the combined treatment synergistically suppressed thyroid tumor growth by attenuating STAT3 and ERK signaling, resulting in decreased anti-apoptotic key regulators such as Mc...

Source: Endocrine-Related Cancer - July 24, 2018 Category: Endocrinology Authors: Park, S., Willingham, M. C., Qi, J., Cheng, S.-Y. Tags: Research Source Type: research