Palbociclib suppresses the cancer stem cell properties and cell proliferation through increased levels of miR-506 or miR-150 in Panc-1 and MiaPaCa-2 cells.

Özge Rencüzoğullari, Elif Damla Arisan
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Abstract

The prognostic characteristics of pancreatic cancer (PC) are determined by the contributing factors from the tumor microenvironment. Leptin is a critical oncogenic factor released by adipocytes as an adipokine into the tumor microenvironment, where it promotes tumor development by activating cancer stem cell (CSC) molecular regulators Notch, Hedgehog, and Wnt/β-catenin signaling. One of the downstream targets of these pathways is CDK4/6 and cyclin D which is controlled by P16 INK4A that is highly mutated in PC. Therefore, the purpose of this study was to determine the effect of a CDK4/6 inhibitor, palbociclib, on Leptin-induced PC cells and to target the Notch, Hedgehog, and Wnt/β-catenin signaling pathways via miR-150, miR-506, and miR-208 modulation. Leptin treatment increased the ability of Panc-1, MiaPaCa-2, and Capan-2 cells to proliferate and decreased the effect of palbociclib. Additionally, tumorspheres were generated from Leptin-treated (Leptin+) and Leptin-untreated (Leptin-) Panc-1 and MiaPaCa-2 cells and transfected with miR-506, miR-150 (tumorsuppressor miRNAs), or anti-miR-208 (oncomiR), followed by palbociclib treatment. Forced expression of miR-506 or miR-150 significantly increased the susceptibility of Leptin+ cells to palbociclib treatment by inhibiting colony and tumor spheroid formation, and CD44 expression in Panc-1 and MiaPaCa-2 cells. Additionally, the increased miR-150 expression is more effective at inhibiting N-cadherin, β-catenin, p-GSK3β, Notch, and Wnt5a/b expression in Leptin-/+ Panc-1 and MiaPaCa-2 cells. As a result, palbociclib suppressed the CSC profile induced by leptin treatment, inhibiting both tumorsphere forms and leptin-targeted signaling pathways, thereby disabling the Panc-1 and MiaPaCa-2 cells' resistance mechanism. Increased expression of miR-506 or miR-150 and inhibition of miR-208 enhanced sensitivity of Panc-1 and MiaPaCa-2 Leptin-/+ cells to palbociclib treatment. As a result, this study proved that combining inhibitors of CSC molecular regulators with palbociclib improves the success rate of inhibition of PC cell proliferation.

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Palbociclib通过增加Panc-1和MiaPaCa-2细胞中miR-506或miR-150的水平来抑制癌症干细胞特性和细胞增殖。
胰腺癌(PC)的预后特征是由肿瘤微环境的影响因素决定的。瘦素是一种重要的致癌因子,由脂肪细胞作为脂肪因子释放到肿瘤微环境中,通过激活癌症干细胞(CSC)分子调控因子Notch、Hedgehog和Wnt/β-catenin信号通路促进肿瘤发展。这些途径的下游靶点之一是CDK4/6和细胞周期蛋白D,它们由在PC中高度突变的P16 INK4A控制。因此,本研究的目的是确定CDK4/6抑制剂palbociclib对leptin诱导的PC细胞的影响,并通过miR-150、miR-506和miR-208调节Notch、Hedgehog和Wnt/β-catenin信号通路。瘦素治疗增加了Panc-1、MiaPaCa-2和Capan-2细胞的增殖能力,降低了帕博西尼的作用。此外,从Leptin处理(Leptin+)和Leptin未处理(Leptin-)的Panc-1和miapca -2细胞中产生肿瘤球,并转染miR-506, miR-150(肿瘤抑制mirna)或anti-miR-208 (oncomiR),然后进行帕博西尼治疗。强制表达miR-506或miR-150通过抑制集落和肿瘤球体形成,以及Panc-1和miapca -2细胞中CD44的表达,显著增加Leptin+细胞对帕博西尼治疗的易感性。此外,miR-150表达的增加更有效地抑制N-cadherin、β-catenin、p-GSK3β、Notch和Wnt5a/b在Leptin-/+ Panc-1和MiaPaCa-2细胞中的表达。因此,palbociclib抑制了瘦素治疗诱导的CSC谱,抑制了肿瘤球形态和瘦素靶向信号通路,从而使Panc-1和MiaPaCa-2细胞的耐药机制失效。miR-506或miR-150的表达增加以及miR-208的抑制增强了Panc-1和MiaPaCa-2瘦素-/+细胞对帕博西尼治疗的敏感性。因此,本研究证明CSC分子调节因子抑制剂与palbociclib联合使用可提高抑制PC细胞增殖的成功率。
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