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

doi:10.55730/1300-0152.2622

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

Turk J Biol. 2022 Jul 18;46(5):342-360. doi: 10.55730/1300-0152.2622. eCollection 2022.

Authors

Özge Rencüzoğullari¹, Elif Damla Arisan²

Affiliations

¹ İstanbul Kültür University, Science and Literature Faculty, Department of Molecular Biology and Genetics, İstanbul, Turkey.
² Institute of Biotechnology, Gebze Technical University, Gebze, Turkey.

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.

Keywords: CDK4/6 inhibitor; Pancreatic cancer; Wnt/ β-catenin; leptin; miR-150; miR-208; miR-506.

Grants and funding

This research was funded by TÜBİTAK under grant number 119Z158 and by İstanbul Kültür University Scientific Project Center.