Multi-OMIC profiling of survival and metabolic signaling networks in cells subjected to photodynamic therapy.

Abstract

Photodynamic therapy (PDT) is an established palliative treatment for perihilar cholangiocarcinoma that is clinically promising. However, tumors tend to regrow after PDT, which may result from the PDT-induced activation of survival pathways in sublethally afflicted tumor cells. In this study, tumor-comprising cells (i.e., vascular endothelial cells, macrophages, perihilar cholangiocarcinoma cells, and EGFR-overexpressing epidermoid cancer cells) were treated with the photosensitizer zinc phthalocyanine that was encapsulated in cationic liposomes (ZPCLs). The post-PDT survival pathways and metabolism were studied following sublethal (LC50) and supralethal (LC90) PDT. Sublethal PDT induced survival signaling in perihilar cholangiocarcinoma (SK-ChA-1) cells via mainly HIF-1-, NF-кB-, AP-1-, and heat shock factor (HSF)-mediated pathways. In contrast, supralethal PDT damage was associated with a dampened survival response. PDT-subjected SK-ChA-1 cells downregulated proteins associated with EGFR signaling, particularly at LC90. PDT also affected various components of glycolysis and the tricarboxylic acid cycle as well as metabolites involved in redox signaling. In conclusion, sublethal PDT activates multiple pathways in tumor-associated cell types that transcriptionally regulate cell survival, proliferation, energy metabolism, detoxification, inflammation/angiogenesis, and metastasis. Accordingly, tumor cells sublethally afflicted by PDT are a major therapeutic culprit. Our multi-omic analysis further unveiled multiple druggable targets for pharmacological co-intervention.

• Authors: Ruud Weijer, Séverine Clavier, Esther A Zaal, Maud M E Pijls, Robert T van Kooten, Klaas Vermaas, René Leen, Aldo Jongejan, Perry D Moerland, Antoine H C van Kampen, André B P van Kuilenburg, Celia R Berkers, Simone Lemeer, Michal Heger
• Journal: Cellular and molecular life sciences : CMLS (Cell Mol Life Sci) Vol. 74 Issue 6 Pg. 1133-1151 (03 2017) ISSN: 1420-9071 [Electronic] Switzerland
• PMID: 27803950 (Publication Type: Journal Article)

Chemical References

• Photosensitizing Agents
• ErbB Receptors

Topics

• Animals
• Cell Death (drug effects)
• Cell Line
• Cell Survival (drug effects)
• Down-Regulation (drug effects)
• Energy Metabolism (drug effects)
• ErbB Receptors (metabolism)
• Humans
• Metabolic Networks and Pathways (drug effects)
• Metabolome (drug effects)
• Metabolomics (methods)
• Mice
• Oxidation-Reduction (drug effects)
• Photochemotherapy
• Photosensitizing Agents (pharmacology)
• Proteomics (methods)
• Signal Transduction (drug effects)
• Time Factors
• Transcription, Genetic (drug effects)
• Up-Regulation (drug effects)