Pancreatic cancer is a challenging malignancy, mainly due to aggressive regional involvement, early systemic dissemination, high recurrence rate, and subsequent low patient survival. Scientific advances have contributed in particular by identification of molecular targets as well as the definition of the mechanism of action of the drug candidate in the cellular microenvironment. Previously, we have reported the identification of the molecular mechanisms by which calix[6]arene (CLX6) reduces the viability and proliferation of pancreatic cancer cells. Now, we show the biochemical mechanisms by which CLX6 decreases the aggressiveness of Panc-1 cells, focusing specifically on receptor tyrosine kinases (RTK). The results show that clathrin-mediated endocytosis is involved in CLX6-induced AXL receptor tyrosine kinase degradation in Panc-1 cells. This response may be related to the interaction of CLX6 with the tyrosine kinase receptor binding site (such as AXL). As a result, RTK is internalized and degraded by endocytosis, a condition that negatively impacts events dependent on its signaling. Additionally, CLX6 inhibits migration and invasion of Panc-1 cells by downregulating FAK (downstream mediator of AXL) activity and reducing expression levels of MMP2 and MMP9, directly related to the metastatic profile of these cells. It is noteworthy that according to the mechanism proposed here, CLX6 appears as a candidate to be used in therapeutic protocols of patients that display high expression of AXL and consequently, poor diagnosis.

中文翻译：

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Calix[6]arene 缩短了胰腺癌细胞中受体酪氨酸激酶的寿命，并抑制了它们的迁移和侵袭效率。

胰腺癌是一种具有挑战性的恶性肿瘤，主要是由于侵袭性区域受累、早期全身播散、高复发率和随后的低患者存活率。科学进步尤其有助于识别分子靶点以及定义候选药物在细胞微环境中的作用机制。以前，我们已经报道了杯 [6] 芳烃 (CLX6) 降低胰腺癌细胞活力和增殖的分子机制的鉴定。现在，我们展示了 CLX6 降低 Panc-1 细胞侵袭性的生化机制，特别关注受体酪氨酸激酶 (RTK)。结果表明，网格蛋白介导的内吞作用参与了 CLX6 诱导的 AXL 受体酪氨酸激酶在 Panc-1 细胞中的降解。这种反应可能与 CLX6 与酪氨酸激酶受体结合位点（如 AXL）的相互作用有关。因此，RTK 被内吞作用内化和降解，这种情况会对依赖于其信号的事件产生负面影响。此外，CLX6 通过下调 FAK（AXL 的下游介质）活性和降低与这些细胞的转移情况直接相关的 MMP2 和 MMP9 的表达水平来抑制 Panc-1 细胞的迁移和侵袭。值得注意的是，根据此处提出的机制，CLX6 似乎可用于显示 AXL 高表达并因此诊断不佳的患者的治疗方案。RTK 被内吞作用内化和降解，这种情况会对依赖于其信号的事件产生负面影响。此外，CLX6 通过下调 FAK（AXL 的下游介质）活性和降低与这些细胞的转移情况直接相关的 MMP2 和 MMP9 的表达水平来抑制 Panc-1 细胞的迁移和侵袭。值得注意的是，根据此处提出的机制，CLX6 似乎可用于显示 AXL 高表达并因此诊断不佳的患者的治疗方案。RTK 被内吞作用内化和降解，这种情况会对依赖于其信号的事件产生负面影响。此外，CLX6 通过下调 FAK（AXL 的下游介质）活性和降低与这些细胞的转移情况直接相关的 MMP2 和 MMP9 的表达水平来抑制 Panc-1 细胞的迁移和侵袭。值得注意的是，根据此处提出的机制，CLX6 似乎可用于显示 AXL 高表达并因此诊断不佳的患者的治疗方案。与这些细胞的转移情况直接相关。值得注意的是，根据此处提出的机制，CLX6 似乎可用于显示 AXL 高表达并因此诊断不佳的患者的治疗方案。与这些细胞的转移情况直接相关。值得注意的是，根据此处提出的机制，CLX6 似乎可用于显示 AXL 高表达并因此诊断不佳的患者的治疗方案。