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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-016-2401-0) contains supplementary material, which is available to authorized users.

Post-illumination cellular effects of photodynamic treatment

“…These results are in line with a previous report demonstrating that at LD 50 , a lipophilic phthalocyanine PS localizing to mitochondrial membranes, caused a time-dependent loss of metabolic activity and viability within a 24 period after illumination [ 11 ]. The authors concluded that reactions leading to suppression of metabolism and activation of cell death pathways progressed for at least 24 h after PDT [ 11 ].…”

“…Since dead cells detach and are removed with the medium before fixation, SRB stains only viable, attached cells. SRB staining is thus considered a suitable method to estimate fully executed cell death [ 11 ].…”

“…The fate of such mildly injured cells will depend on whether cell survival stress response (reviewed in [ 10 ]) or cell-destruction reactions will prevail. It has been demonstrated that sub-lethal PDT leads to activation of cellular pathways that regulate metabolism, proliferation, metastasis, and survival [ 11 ]. Activation of survival pathways is considered a major cause for resistance to anti-cancer treatment.…”

Dihydroartemisinin Increases the Sensitivity of Photodynamic Therapy Via NF-κB/HIF-1α/VEGF Pathway in Esophageal Cancer Cell in vitro and in vivo

“…Esophageal cancer has high morbidity and mortality, partly because patients tend to be diagnosed at an advanced stage and with esophageal obstruction, which seriously affects their quality of life. Thankfully, an effective medical treatment, PDT, has been found to relieve the esophageal obstruction by inducing localized tumor destruction via the photochemical generation of cytotoxic singlet oxygen [15][16][17][18][19].…”

Coagulation cascade and complement system in systemic lupus erythematosus

“…These studies provide more information on the pathogenic pathways, but they are all based on a single omics platform and cannot reveal the links for the components of signaling pathways at transcript, protein and metabolite levels. Given that many signaling pathways are orchestrated by global networks that cut across multiple omics layers [ 10 ], the researchers have recently begun to integrate the multi-omics data measured in a certain experiment to give a much more detailed view of signaling pathways than when applied individually [ 11 – 13 ]. However, to date no researcher has comprehensively integrated these diverse sets of data to study SLE.…”