Department of Radiation Oncology, 4th affiliated hospital, China Medical University, Shenyang, China.
Oncogene. 2013 May 23;32(21):2682-9. doi: 10.1038/onc.2012.279. Epub 2012 Jul 2.
Skin cancer is the most common cancer in the United States, while DNA-damaging ultraviolet B (UVB) radiation from the sun remains the major environmental risk factor. Reducing skin cancer incidence is becoming an urgent issue. The energy-sensing enzyme 5'-AMP-activated protein kinase (AMPK) has a key role in the regulation of cellular lipid and protein metabolism in response to stimuli such as exercise and changes in fuel availability. However, the role of AMPK in the response of skin cells to UVB damage and in skin cancer prevention remains unknown. Here we show that AMPK activation is reduced in human and mouse squamous cell carcinoma as compared with normal skin, and by UVB irradiation, suggesting that AMPK is a tumor suppressor. At the molecular level, AMPK deletion reduced the expression of the DNA repair protein xeroderma pigmentosum C (XPC) and UVB-induced DNA repair. AMPK activation by its activators AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) and metformin (N',N'-dimethylbiguanide), the most widely used antidiabetic drug, increased the expression of XPC and UVB-induced DNA repair in mouse skin, normal human epidermal keratinocytes, and AMPK wild-type (WT) cells but not in AMPK-deficient cells, indicating an AMPK-dependent mechanism. Topical treatment with AICAR and metformin not only delayed onset of UVB-induced skin tumorigenesis but also reduced tumor multiplicity. Furthermore, AMPK deletion increased extracellular signal-regulated kinase (ERK) activation and cell proliferation, whereas AICAR and metformin inhibited ERK activation and cell proliferation in keratinocytes, mouse skin, AMPK WT and AMPK-deficient cells, suggesting an AMPK-independent mechanism. Finally, in UVB-damaged tumor-bearing mice, both topical and systemic metformin prevented the formation of new tumors and suppressed growth of established tumors. Our findings not only suggest that AMPK is a tumor suppressor in the skin by promoting DNA repair and controlling cell proliferation, but also demonstrate previously unknown mechanisms by which the AMPK activators prevent UVB-induced skin tumorigenesis.
皮肤癌是美国最常见的癌症，而来自太阳的 DNA 损伤性紫外线 B（UVB）辐射仍然是主要的环境风险因素。降低皮肤癌的发病率正成为一个紧迫的问题。能量感应酶 5'-AMP 激活蛋白激酶（AMPK）在调节细胞脂质和蛋白质代谢方面起着关键作用，以响应运动和燃料可用性变化等刺激。然而，AMPK 在皮肤细胞对 UVB 损伤的反应以及在皮肤癌预防中的作用尚不清楚。在这里，我们表明与正常皮肤相比，人鳞状细胞癌和小鼠鳞状细胞癌中的 AMPK 活性降低，并且受到 UVB 照射的影响，这表明 AMPK 是一种肿瘤抑制因子。在分子水平上，AMPK 缺失会降低 DNA 修复蛋白 Xeroderma Pigmentosum C（XPC）的表达并减少 UVB 诱导的 DNA 修复。其激活剂 AICAR（5-氨基咪唑-4-甲酰胺核苷）和二甲双胍（N'，N'-二甲基双胍）的 AMPK 激活作用增加了 XPC 的表达和 UVB 诱导的 DNA 修复在小鼠皮肤、正常人类表皮角质形成细胞和 AMPK 野生型（WT）细胞中，但在 AMPK 缺陷型细胞中则不然，表明存在 AMPK 依赖性机制。AICAR 和二甲双胍的局部治疗不仅延迟了 UVB 诱导的皮肤肿瘤发生的开始，而且还降低了肿瘤的多发性。此外，AMPK 缺失增加了细胞外信号调节激酶（ERK）的激活和细胞增殖，而 AICAR 和二甲双胍则抑制了 ERK 的激活和角质形成细胞、小鼠皮肤、AMPK WT 和 AMPK 缺陷型细胞中的细胞增殖，表明存在 AMPK 非依赖性机制。最后，在 UVB 损伤的荷瘤小鼠中，局部和全身使用二甲双胍均可防止新肿瘤的形成并抑制已建立肿瘤的生长。我们的研究结果不仅表明 AMPK 通过促进 DNA 修复和控制细胞增殖而成为皮肤中的肿瘤抑制因子，而且还证明了 AMPK 激活剂预防 UVB 诱导的皮肤肿瘤发生的先前未知的机制。
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