Multi-OMIC profiling of survival and metabolic signaling networks in cells subjected to photodynamic therapy.
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.
Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, Amsterdam, AZ, The Netherlands.
Ruud
R
Weijer
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584, Utrecht, CH, The Netherlands.
Séverine
S
Clavier
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584, Utrecht, CH, The Netherlands.
Esther A
EA
Zaal
Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, Amsterdam, AZ, The Netherlands.
Maud M E
MM
Pijls
Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, Amsterdam, AZ, The Netherlands.
Robert T
RT
van Kooten
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584, Utrecht, CH, The Netherlands.
Klaas
K
Vermaas
Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, Amsterdam, AZ, The Netherlands.
René
R
Leen
Bioinformatics Laboratory, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, Amsterdam, AZ, The Netherlands.
Aldo
A
Jongejan
Bioinformatics Laboratory, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, Amsterdam, AZ, The Netherlands.
Perry D
PD
Moerland
Bioinformatics Laboratory, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, Amsterdam, AZ, The Netherlands.
Antoine H C
AH
van Kampen
Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, Amsterdam, AZ, The Netherlands.
André B P
AB
van Kuilenburg
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584, Utrecht, CH, The Netherlands.
Celia R
CR
Berkers
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584, Utrecht, CH, The Netherlands.
Simone
S
Lemeer
Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, Amsterdam, AZ, The Netherlands. m.heger@amc.uva.nl.
Michal
M
Heger
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D055442:Metabolome / Q000187:drug effects; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D010084:Oxidation-Reduction / Q000187:drug effects; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology; D040901:Proteomics / Q000379:methods*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D017319:Photosensitizing Agents; D066246:ErbB Receptors
Cancer therapy; Metallated phthalocyanines; Non-resectable perihilar cholangiocarcinoma; Reactive oxygen species; Therapeutic recalcitrance; Tumor targeting