Nab-Paclitaxel Promotes Radiosensitization by Inducing DNA Damage and Inhibiting Macrophage M2 Polarization in Cholangiocarcinoma

Abstract

Background:

Nab-paclitaxel effectively inhibits tumor proliferation and modulates macrophage polarization to improve the tumor microenvironment. However, its potential to achieve radiosensitization in cholangiocarcinoma remains to be elucidated.

Materials and Methods:

The proliferation inhibition and radiosensitizing effects of nab-paclitaxel were assessed using cell counting kit-8 and colony formation assays in NOZ and TFK1 cell lines. Cell apoptosis, cell cycle progression, DNA damage, and macrophage polarization status were analyzed via flow cytometry immunofluorescence, enzyme-linked immunosorbent assay, and qRT-PCR. A tumor-bearing mouse model was established to validate radiosensitization in vivo. Potentially related genes and proteins involved in nab-paclitaxel-induced radiosensitization were identified through RNA transcriptome sequencing and Western blotting.

Results:

Nab-paclitaxel exhibited significant radiosensitizing effects on cholangiocarcinoma cells. Combined with radiotherapy, nab-paclitaxel increased DNA damage, promoted apoptosis, and effectively inhibited M2 polarization of macrophages in vivo and in vitro. The radiosensitizing effect is involved in the activation of the AMP-dependent protein kinase (AMPK) signaling pathway. Nab-paclitaxel significantly upregulated phosphorylated AMPKα, apoptotic proteins as zinc finger matrin-type 3, and nuclear factor kappa-B levels following radiation exposure.

Conclusions:

Our study confirmed the radiosensitizing effect of nab-paclitaxel on cholangiocarcinoma cells through a dual effect of antitumor proliferation and inhibition of M2 macrophage polarization, and the underlying mechanism involved activation of the AMPK signaling pathway.