Ciołczyk-Wierzbicka Dorota, Sikorska-Duplicka Martyna, Zarzycka Marta, Zemanek Grzegorz, Wierzbicki Karol
Center for Medical Genomics-OMICRON, Jagiellonian University Medical College, ul. Kopernika 7c, 31-034 Kraków, Poland.
John Paul II Hospital, ul. Prądnicka 80, 31-202 Kraków, Poland.
Int J Mol Sci. 2025 Aug 12;26(16):7770. doi: 10.3390/ijms26167770.
Melanoma is one of the most invasive skin cancers with the highest mortality risk. The PI3K/AKT/mTOR signaling pathways are a key regulatory point related to growth factors and involved in the cell's energy metabolism. They are responsible for cell life processes such as growth, proliferation, invasion, survival, apoptosis, autophagy, and angiogenesis. The studies undertaken concerned the effect of protein kinase inhibitors involved in the signaling pathways of AKT, MEK, and mTOR kinases on the expression of cytoskeletal and extracellular matrix proteins, invasion process, and activities of the matrix metalloproteinases (MMPs): MMP-2 and MMP-9 in melanoma cells. The study used mTOR kinase inhibitors: Everolimus and Torkinib; dual PI3K/mTOR inhibitors BEZ-235 and Omipalisib; and the mTORC1/2 inhibitor OSI-027. These compounds were used both as monotherapy and in combination with the MEK1/2 inhibitor AS-703026. mTOR kinase inhibitors, especially the third generation in combination with the MEK 1/2 kinase inhibitor AS-703026, significantly inhibited invasion and metalloproteinases (MMPs) activity in melanoma cell lines. The inhibition of the cell invasion process was accompanied by a significant change in the expression of proteins associated with EMT. The morphology of cells also changed significantly: their thickness, volume, roughness, convexity of shape, and irregularity, which may be a good diagnostic and prognostic factor for the response to treatment. Our studies to date on the effect of three generations of mTOR kinase inhibitors on the inhibition of the invasion process, the activation of apoptosis, and the reduction in cell proliferation suggest that they may be an important target for anticancer therapy.
黑色素瘤是侵袭性最强、死亡风险最高的皮肤癌之一。PI3K/AKT/mTOR信号通路是与生长因子相关的关键调控点，参与细胞的能量代谢。它们负责细胞的生长、增殖、侵袭、存活、凋亡、自噬和血管生成等生命过程。所开展的研究关注参与AKT、MEK和mTOR激酶信号通路的蛋白激酶抑制剂对黑色素瘤细胞中细胞骨架和细胞外基质蛋白表达、侵袭过程以及基质金属蛋白酶（MMPs）：MMP-2和MMP-9活性的影响。该研究使用了mTOR激酶抑制剂：依维莫司和托瑞替尼；双PI3K/mTOR抑制剂BEZ-235和奥米帕利司；以及mTORC1/2抑制剂OSI-027。这些化合物既作为单一疗法使用，也与MEK1/2抑制剂AS-703026联合使用。mTOR激酶抑制剂，尤其是第三代与MEK 1/2激酶抑制剂AS-703026联合使用时，能显著抑制黑色素瘤细胞系的侵袭和金属蛋白酶（MMPs）活性。细胞侵袭过程的抑制伴随着与上皮-间质转化相关蛋白表达 的显著变化。细胞形态也发生了显著改变：其厚度、体积、粗糙度、形状凸度和不规则性，这可能是治疗反应的良好诊断和预后因素。我们目前关于三代mTOR激酶抑制剂对侵袭过程抑制、凋亡激活和细胞增殖减少作用的研究表明，它们可能是抗癌治疗的重要靶点。
