Expression profiles of heme synthesis metabolite transporters as potential molecular determinants of sensitivity to 5‑ALA‑induced PDT

Expression profiles of transporters of heme synthesis metabolites can be used as potential molecular determinants defining the variable sensitivity of tumor cells to photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA). The study included the JFCR39 panel of human cell lines. Transcriptional activity profiles of genes encoding nine key transporter proteins (SLC15A1, SLC36A1, SLC6A6, SLC6A13, TSPO1/2, ABCG2, ABCB6, FLVCR1, SLC25A37) were obtained from The Human Protein Atlas (HPA) database. For quantitative assessment, the nTPM (normalized transcripts per million) metric was used. Data on protoporphyrin IX (PPIX) accumulation levels after incubation of cells with 1 mM 5-ALA were taken from the published screening by Kitajima Y. et al. (2019). Statistical significance of associations was assessed using Pearson correlation analysis. A pronounced tissue specificity of correlations between transporter expression and intracellular PPIX accumulation was established. In the brain tumor panel, a very strong negative association of PPIX levels with the expression of the iron transporter MFRN (SLC25A37; R = -0.91 to -0.96) and the ATP-binding cassette transporter ABCB6 (-0.94) was revealed, which may indicate a critical role of mitochondrial iron uptake and tetrapyrrole efflux in glioma resistance to PDT. At the same time, for the classic 5-ALA transporters themselves (PEPT1, PAT1, TauT, GAT2), no statistically significant positive association with the photosensitizer level was found either across the entire panel or in most nosologies. An exception was ovarian cancer lines, where PAT1 expression demonstrated a moderate positive correlation with PPIX accumulation (R = 0.62–0.75). Comparison of efflux transporters showed that the contribution of ABCB6 to the reduction of PPIX concentration is comparable to or exceeds that of the recognized marker ABCG2, especially in lines of neuroectodermal origin.

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