Effect of Photodynamic Therapy on Gemcitabine-Resistant Cholangiocarcinoma in vitro and in vivo Through KLF10 and EGFR

Abstract

Cholangiocarcinoma is a relatively rare neoplasm with increasing incidence. Although chemotherapeutic agent such as gemcitabine has long been used as standard treatment for cholangiocarcinoma, the interindividual variability in target and drug sensitivity and specificity may lead to therapeutic resistance. In the present study, we found that photodynamic therapy (PDT) treatment inhibited gemcitabine-resistant cholangiocarcinoma cells via repressing cell viability, enhancing cell apoptosis, and eliciting G1 cell cycle arrest through modulating Cyclin D1 and caspase 3 cleavage. In vivo, PDT treatment significantly inhibited the growth of gemcitabine-resistant cholangiocarcinoma cell-derived tumors. Online data mining and experimental analyses indicate that KLF10 expression was induced, whereas EGFR expression was downregulated by PDT treatment; KLF10 targeted the EGFR promoter region to inhibit EGFR transcription. Under PDT treatment, EGFR overexpression and KLF10 silencing attenuated the anti-cancer effects of PDT on gemcitabine-resistant cholangiocarcinoma cells by promoting cell viability, inhibiting apoptosis, and increasing S phase cell proportion. Importantly, under PDT treatment, the effects of KLF10 silencing were significantly reversed by EGFR silencing. In conclusion, PDT treatment induces KLF10 expression and downregulates EGFR expression. KLF10 binds to EGFR promoter region to inhibit EGFR transcription. The KLF10/EGFR axis participates in the process of the inhibition of PDT on gemcitabine-resistant cholangiocarcinoma cells.

Krüppel-like Factor 10 as a Prognostic and Predictive Biomarker of Radiotherapy in Pancreatic Adenocarcinoma

“…Radiation-induced KLF10 upregulation was noted in many cancer cell lines and murine models [83][84][85]. KLF10 transcriptionally downregulated EGFR and modulated gemcitabine-resistance in cholangiocarcinoma [86]. In esophageal squamous cell carcinoma, exosomes secreted from hypoxic tumors after radiation expressed high levels of miR-340-5p, which suppressed KLF10 transcription.…”

Photodynamic therapy induced cell cycle arrest and cancer cell synchronization: review

“…Furthermore, in vitro experiments of Gemcitabine and PDT showed that cholangiocarcinoma induces repressing cell viability, apoptosis, and eliciting of CCA in G1 phase via modulating cyclin D1 and caspase 3 cleavage. and prevents tumor growth in vivo ( 147 ). In addition, Mascaraque and colleagues evaluated the PS ability of metformin (Metf) on BCC cells.…”

Surufatinib combined with photodynamic therapy induces ferroptosis to inhibit cholangiocarcinoma in vitro and in tumor models

“…PDT has been listed in the guidelines of the National Comprehensive Cancer Network (NCCN) of CCA (Benson et al, 2014). It has been found that PDT can kill cholangiocarcinoma cells by inhibiting cell cycle and promoting apoptosis (Yang et al, 2021). Simultaneously, multi-kinase inhibitors targeting Ras, Raf, vascular endothelial growth factor and fibroblast growth factor receptor can also generate ROS and have certain anti-CCA effects, improving the prognosis of metastatic/unresectable patients (Xie et al, 2016;Cousin et al, 2022).…”