Department of Biochemistry, Kasetsart University, Chatuchak, Bangkok, 10900, Thailand.
Department of Biochemistry, Mahidol University, Ratchathewi, Bangkok, 10400, Thailand.
Exp Cell Res. 2021 Sep 15;406(2):112765. doi: 10.1016/j.yexcr.2021.112765. Epub 2021 Aug 4.
Nasopharyngeal carcinoma (NPC) originates in the nasopharynx epithelium. Although concurrent chemoradiation therapy followed by chemotherapy is considered as an effective treatment, there is substantial drug resistance in locally advanced NPC patients. One major contributor to the chemoresistance includes aberrant expression of cell adhesion molecules, such as integrin α and β subunits, giving rise to cell adhesion-mediated drug resistance. Thus, the aim of this study was to investigate the effect of integrin α5 on the development of intrinsic cisplatin resistance in NPC and the associated underlying mechanisms using in vitro three-dimensional (3D) spheroid models, as well as induced cisplatin-resistant NPC (NPCcisR). We demonstrated that established 3D highly- (5-8F) and lowly- (6-10B) metastatic NPC spheroids overexpressed integrin α5 and aggravated their resistance to cisplatin. Besides, enhanced integrin α5 resulted in substantially reduced growth, corresponding to G/G and G/M cell cycle arrest. In addition, 5-8FcisR and 6-10BcisR cells in 3D forms synergistically strengthened endurance of their spheroids to cisplatin treatment as observed by increased resistance index (RI) and decreased apoptosis. Mechanistically, the aberrantly expressed integrin α5 decreased drug susceptibility in NPC spheroids by inactivating ERK and inhibition of caspase-3 inducing apoptosis. Furthermore, the effect of integrin α5 inducing intrinsic resistance was verified via treatment with ATN-161, a peptide inhibitor for integrin α5β1. The results showed dramatic reduction in integrin α5 expression, reversal of ERK phosphorylation and caspase-3 cleavage, together with elevated cisplatin sensitivity, indicating regulation of innate drug resistance via integrin α5. Taken together, our findings suggest that integrin α5 could act as a promising target to enhance the chemotherapeutic sensitivity in NPC.
鼻咽癌（NPC）起源于鼻咽部上皮。尽管同步放化疗后再辅以化疗被认为是一种有效的治疗方法，但局部晚期 NPC 患者存在明显的药物耐药性。细胞黏附分子（如整合素α和β亚基）的异常表达是导致化疗耐药的主要原因之一，从而导致细胞黏附介导的耐药性。因此，本研究旨在通过体外三维（3D）球体模型以及诱导的顺铂耐药鼻咽癌（NPCcisR）研究整合素α5对 NPC 内在顺铂耐药性发展的影响及其相关机制。我们证明，已建立的高（5-8F）和低（6-10B）转移性 NPC 球体过度表达整合素α5，并加重了它们对顺铂的耐药性。此外，增强的整合素α5导致细胞生长明显减少，对应于 G/G 和 G/M 细胞周期阻滞。此外，在 3D 形式下，5-8FcisR 和 6-10BcisR 细胞协同增强了它们球体对顺铂治疗的耐受力，表现为耐药指数（RI）增加和凋亡减少。在机制上，异常表达的整合素α5通过使 ERK 失活和抑制 caspase-3 诱导凋亡来降低 NPC 球体的药物敏感性。此外，通过用整合素α5β1的肽抑制剂 ATN-161 处理，验证了整合素α5诱导内在耐药的作用。结果显示，整合素α5表达显著减少，ERK 磷酸化和 caspase-3 切割逆转，以及顺铂敏感性提高，表明通过整合素α5调节内在药物耐药性。总之，我们的研究结果表明，整合素α5可以作为增强鼻咽癌化疗敏感性的有前途的靶点。
