Shin Ye Young, Seo Yoojin, Oh Su-Jeong, Ahn Ji-Su, Song Min-Hye, Kang Min-Jung, Oh Jung-Min, Lee Dongjun, Kim Yun Hak, Sung Eui-Suk, Kim Hyung-Sik
Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Korea.
Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan, Korea.
J Pineal Res. 2022 Jan;72(1):e12779. doi: 10.1111/jpi.12779. Epub 2021 Dec 10.
The prevalence of head and neck squamous cell carcinoma (HNSCC) has continued to rise for decades. However, drug resistance to chemotherapeutics and relapse, mediated by cancer stem cells (CSCs), remains a significant impediment in clinical oncology to achieve successful treatment. Therefore, we focused on analyzing CSCs in HNSCC and demonstrated the effect of melatonin (Mel) and verteporfin (VP) on SCC-25 cells. HNSCC CSCs were enriched in the reactive oxygen species-low state and in sphere-forming cultures. Combination treatment with Mel and VP decreased HNSCC viability and increased apoptosis without causing significant damage to normal cells. Sphere-forming ability and stem cell population were reduced by co-treatment with Mel and VP, while mitochondrial ROS level was increased by the treatment. Furthermore, the expression of mitophagy markers, parkin and PINK1, was significantly decreased in the co-treated cells. Mel and VP induced mitochondrial depolarization and inhibited mitochondrial function. Parkin/TOM20 was localized near the nucleus and formed clusters of mitochondria in the cells after treatment. Moreover, Mel and VP downregulated the expression of markers involved in epithelial-mesenchymal transition and metastasis. The migration capacity of cells was significantly decreased by co-treatment with Mel and VP, accompanied by the down-regulation of MMP-2 and MMP-9 expression. Taken together, these results indicate that co-treatment with Mel and VP induces mitochondrial dysfunction, resulting in the apoptosis of CSCs. Mel and VP could thus be further investigated as potential therapies for HNSCC through their action on CSCs.
数十年来，头颈部鳞状细胞癌（HNSCC）的患病率持续上升。然而，由癌症干细胞（CSC）介导的对化疗药物的耐药性和复发，仍然是临床肿瘤学中实现成功治疗的重大障碍。因此，我们专注于分析HNSCC中的CSC，并证明了褪黑素（Mel）和维替泊芬（VP）对SCC - 25细胞的作用。HNSCC CSC在活性氧低状态和球形形成培养物中富集。Mel和VP联合治疗降低了HNSCC的活力并增加了细胞凋亡，而不会对正常细胞造成显著损害。Mel和VP联合处理降低了球形形成能力和干细胞群体，同时处理增加了线粒体ROS水平。此外，在联合处理的细胞中，线粒体自噬标记物帕金蛋白（parkin）和PTEN诱导激酶1（PINK1）的表达显著降低。Mel和VP诱导线粒体去极化并抑制线粒体功能。处理后，帕金蛋白/线粒体外膜转位酶20（Parkin/TOM20）定位于细胞核附近并在细胞中形成线粒体簇。此外，Mel和VP下调了参与上皮-间质转化和转移的标记物的表达。Mel和VP联合处理显著降低了细胞的迁移能力，同时伴随着基质金属蛋白酶-2（MMP - 2）和基质金属蛋白酶-9（MMP - 9）表达的下调。综上所述，这些结果表明Mel和VP联合处理诱导线粒体功能障碍，导致CSC凋亡。因此，通过它们对CSC的作用，Mel和VP可作为HNSCC的潜在治疗方法进行进一步研究。
