Bi Suyun, Li Li, Gu Heng, Li Min, Xu Song, Bu Wenbo, Zhang Mengli, Zhou Zhihai, Chen Xu
Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, 210042, China.
Dermatology and Venereology Department, Tianjin Medical University General Hospital, Tianjin, China.
J Cancer. 2019 Jan 1;10(2):510-521. doi: 10.7150/jca.26578. eCollection 2019.
Lycopene, a kind of carotenoid, has been reported to have an inhibitory function on tumor cell migration. However, the potential role of lycopene in the treatment of cutaneous squamous cell carcinoma (cSCC) remains unclear. Therefore, we assessed the biological effects of lycopene in the human cSCC cell line COLO-16, human epidermal keratinocytes (HEKs) and the immortalized human keratinocyte cell line HaCaT. We found that lycopene inhibited the cell proliferation and migration of COLO-16 cells but not normal keratinocytes. In addition, lycopene upregulated the protein levels of ZO-1 in COLO-16 and HaCaT cells but not in HEKs. In contrast, lycopene upregulated the protein level of claudin-1 in HEKs but downregulated claudin-1 in COLO-16 cells. Lycopene led to a decrease in autophagic flux in COLO-16 cells in a mechanistic target of rapamycin complex 1 (MTORC1)-dependent manner. Importantly, autophagy inhibition contributed to the lycopene-induced regulation on ZO-1 and claudin-1 in COLO-16 cells. Moreover, JNK inhibitor (SP600125) and MEK inhibitor (U0126) treatment abolished the increase in phosphorylated MTOR and ribosomal protein S6 as well as the increase in ZO-1 and the decrease in claudin-1 in lycopene-treated COLO-16 cells. Gene silencing of JNK and ERK also prohibited ZO-1 upregulation and claudin-1 downregulation. In conclusion, lycopene upregulates ZO-1 expression and downregulates claudin-1 expression through the activation of ERK, JNK and MTORC1 as well as the inhibition of autophagy in human cSCC cells. Our findings demonstrate that autophagy plays a key role in lycopene-mediated pharmacological effects. This study indicates that lycopene might be a useful chemopreventive agent against cSCC.
番茄红素是一种类胡萝卜素，据报道其对肿瘤细胞迁移具有抑制作用。然而，番茄红素在皮肤鳞状细胞癌（cSCC）治疗中的潜在作用仍不清楚。因此，我们评估了番茄红素对人cSCC细胞系COLO - 16、人表皮角质形成细胞（HEK）和永生化人角质形成细胞系HaCaT的生物学效应。我们发现番茄红素抑制COLO - 16细胞的增殖和迁移，但对正常角质形成细胞无此作用。此外，番茄红素上调COLO - 16和HaCaT细胞中ZO - 1的蛋白水平，但对HEK细胞无此作用。相反，番茄红素上调HEK细胞中claudin - 1的蛋白水平，但下调COLO - 16细胞中claudin - 1的水平。番茄红素以雷帕霉素复合物1（MTORC1）依赖的方式导致COLO - 16细胞自噬通量降低。重要的是，自噬抑制有助于番茄红素对COLO - 16细胞中ZO - 1和claudin - 1的诱导调节。此外，JNK抑制剂（SP600125）和MEK抑制剂（U0126）处理消除了番茄红素处理的COLO - 16细胞中磷酸化MTOR和核糖体蛋白S6的增加以及ZO - 1的增加和claudin - 1的减少。JNK和ERK的基因沉默也阻止了ZO - 1的上调和claudin - 1的下调。总之，番茄红素通过激活ERK、JNK和MTORC1以及抑制人cSCC细胞中的自噬来上调ZO - 1表达并下调claudin - 1表达。我们的研究结果表明自噬在番茄红素介导的药理作用中起关键作用。这项研究表明番茄红素可能是一种有用的预防cSCC的化学预防剂。
