Metformin and JQ1 synergistically inhibit obesity-activated thyroid cancer

in Endocrine-Related Cancer
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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 Mcl-1, Bcl-2 and survivin and increased pro-apoptotic regulators such as Bim, BAD and cleave caspase 3. Furthermore, combined treatment of JQ1 and metformin reduced cMyc protein levels to suppress vascular invasion, anaplasia and lung metastasis. These findings indicate that combined treatment is more effective than metformin alone and suggest a novel treatment modality for obesity-activated thyroid cancer.

 

      Society for Endocrinology

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    Effects of metformin, JQ1 and combined treatment on survival and thyroid tumor growth of HFD-Thrb PV/PV Pten +/ mice. (A) Survival curves for HFD-Thrb PV/PV Pten +/ mice treated with vehicle control (open circle, n = 15), metformin (closed circles, n = 11), JQ1 (open square; n = 12) or combination treatment of metformin with JQ1 (closed square, n = 11). Mice were treated high-fat diet (HFD) and metformin (0.5 mg/kg/mouse) from the age of 6 weeks until the age of 20 weeks (the study’s end). JQ1 (50 mg/kg/mouse) was administrated i.p. 5 times a week from age 17 weeks to the end of study (20 weeks). Survival data are shown as a Kaplan–Meier plot and analyzed by log-rank test. The difference in survival was significant between mice between combined treatment and mice treated with vehicle (P = 0.0473), but was not significant between mice treated with vehicle and mice treated with metformin or JQ1. (B) Body weight (panel a) and thyroid weight (panel b) and ratios of thyroid weight to total body weight (panel c) were compared for the mice treated with vehicle, metformin only, JQ1 only and a combination of metformin with JQ1 (n = 9–11). Values are means ± s.e.m. The P values are indicated. NS = not significant.

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    Metformin, JQ1 and combined treatment inhibit STAT3 and ERK1/2 activation in the thyroid tumors of HFD-Thrb PV/PV Pten +/ mice. (A-I). Western blot analysis for p-STAT3 (Y705) (panel a), total STAT3 (panel b), Mcl-1 (panel c), Bcl-2 (panel d), survivin (panel e) and GAPDH (panel f) in the thyroids of HFD-Thrb PV/PV Pten +/ mice treated with control, metformin, JQ1 or combination treatment, respectively. GAPDH used as a loading control (n = 3–6 for each group). (A-II) The band intensities from western blot analysis detected in (A-I) were quantified by Image J analysis. Ratios of p-STAT3 vs total STAT3 (panel a), Mcl-1 (panel b), Bcl-2 (panel c) and survivin (panel d). All band intensities were normalized using GAPDH as a loading control. Values are shown as means ± s.e.m. The P values are indicated. (B-I) Western blot analysis for p-ERK1/2 (Thr202/Tyr204) (panel a), total ERK1/2 (panel b), Bim (panel c), BAD (panel d) and GAPDH (panel e) in the thyroids of HFD-Thrb PV/PV Pten +/ mice treated with control, metformin, JQ1 or combination treatment, respectively. GAPDH used as a loading control (n = 3–6 for each group). Values are shown as means ± s.e.m. (B-II) The band intensities from western blot analysis detected in (B-I) were quantified by Image J analysis. Ratios of p-ERK1/2 vs total ERK1/2 (panel a), Bim (panel b) and BAD (panel c) are indicated. All band intensities were normalized using GAPDH as a loading control. Values are shown as means ± s.e.m. The P values are indicated. (C-I) Immunohistochemical analysis for cleaved caspase 3 was carried out in the thyroid sections from the control (panel b), metformin (panel d), JQ1 (panel f) and combined treatment (panel h) of HFD-Thrb PV/PV Pten +/ mice. The representative positively stained cells are marked by arrows. The negative control panels using IgG are shown in the corresponding panels (panel a, c, e and g). (C-II) The cleaved caspase 3 positively stained cells were quantified as percentage of cleaved caspase 3-positive cells vs total cells. The P values are indicated.

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    Combined treatment of metformin and JQ1 synergistically decreases thyroid tumor progression and lung metastasis in HFD-Thrb PV/PV Pten +/ mice. (A-I) The prevalence of hyperplasia (panel a), capsular invasion (panel b), vascular invasion (panel c) and anaplasia (panel d) in the thyroid tumors of HFD-Thrb PV/PV Pten +/ mice treated with vehicle, metformin, JQ1 or combination treatment is shown as percentage of occurrence. *Represents no occurrence (n = 10–16). P values were obtained by Fisher’s exact test. (A-II) Capsular invasion is shown in samples from vehicle (panel a) and metformin treatment alone (panel b) (arrows), but is absent in samples from JQ1 alone (panel c) and combined treatment of JQ1 plus metformin (panel d), showing intact capsules at the margins of tumors (panels c and d). Vascular invasion is demonstrated in vehicle- (panel e) and metformin-treated tumors (panel f) (arrows show tumor cells in vascular lumens). No tumor cells are seen in vascular spaces in JQ1 (panel g) or combined treatment (panel h). Anaplastic foci (arrows) are evident in vehicle (panel i) and metformin-alone treatment (panel j), but no anaplastic foci are seen in JQ1 (panel k) or combined treatment (l). Magnification: panels a–h = ×50; i–l = ×100). (B) The trend in the occurrence of lung metastasis in HFD-Thrb PV/PV Pten +/ mice after treatment with vehicle, metformin, JQ1 and combination treatment is shown (n = 9–11).

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    Metformin, JQ1 and combination treatment decrease the expression of key regulators of EMT in the thyroid tumors of HFD-Thrb PV/PV Pten +/ mice. (A) Western blot analysis for cMyc (panel a), MMP9 (panel b), vimentin (panel c), N-cadherin (panel d), fibronectin (panel e), E-cadherin (panel g) and GAPDH (panel f and h) in the thyroid tumors of HFD-Thrb PV/PV Pten +/ mice treated with vehicle, metformin, JQ1 and combination treatment. GAPDH used as a loading control (n = 3 for each group). (B) The band intensities from Western blot analysis detected in (A) were quantified by ImageJ analysis. Relative abundance of cMyc (panel a), MMP9 (panel b), vimentin (panel c), N-cadherin (panel d) and fibronectin (panel e), and E-cadherin (panel f) were calculated using the GAPDH as loading control. The P values are indicated.

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    A proposed model to account for the actions by which metformin and JQ1 together inhibit tumor progression in HFD-Thrb PV/PV Pten +/ mice. HFD induces the aberrant activation of STAT3 and ERK signaling to promote thyroid cancer progression in HFD-Thrb PV/PV Pten +/ mice. JQ1 and metformin together act to increase the tumor cell apoptosis by elevating the protein levels of pro-apoptotic regulators Bim and BAD and by suppressing the protein levels of anti-apoptotic regulators (Mcl1, Bcl2 and survivin), resulting in increased cleaved caspase 3 activity. Combined treatment of JQ1 and metformin also act to suppress invasion and metastasis by decreasing EMT key regulators (cMyc, MMP9, fibronectin, vimentin, N-cadherin) and increasing E-cadherin protein levels. By acting on these two pathways, JQ1 and metformin together suppress obesity-activated thyroid cancer progression. The extent in the thickness of the lines in the inhibition of pSTAT3 and p-ERK signaling schematically represents the degree of suppression.

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