TMPyP4 promotes cancer cell migration at low doses, but induces cell death at high doses

Photodynamic therapy (PDT) induces cancer cell death (necrosis or apoptosis) mainly by reactive oxygen species (ROS), which are produced by irradiated photosensitizers1. Compared to the conventional anticancer therapy, PDT is less invasive with better tolerance and outcome. In addition, PDT has obvious advantages over other cancer therapeutics such as surgery, radiation and chemotherapy: a minimal functional disturbance, being repetitively applicable on the same site and a low recurrence2. PDT has been rapidly developed over past decades with a great potential to treat multiple types of cancers including esophageal cancer and non-small cell lung cancer3,4. The photosensitizer is crucial for PDT treatment5. However, it has been challenging to obtain an optimal photosensitizer with a high yield of singlet oxygen (1O2) and high precision targeting cancer cells5. TMPyP4 (Fig. 1A), a porphyrins derivative, has been considered as a promising photosensitizer due to its high water solubility, high permeability through cell membrane and preferential accumulation in tumor cells6,7,8. Figure 1 TMPyP4 or TPyP4-Pt treatment results in the change of gene expression profile in A549 cells. Besides potentially serving as a photosensitizer in PDT, TMPyP4 has been recently developed as a chemotherapeutics drug to inhibit telomerase activity in cancer cells9,10,11. About 85% of cancer cells overcome the proliferative limit by activating telomerase, a ribonucleoprotein with reverse transcriptase activity that adds telomeric DNA repeats to the 3′-overhang of telomeres, thus maintaining telomere length and chromosome integrality12. Accumulated evidences show that single-stranded 3′-overhang of telomeres can stack via Hoogsteen hydrogen bonding into a structure referred as G-quadruplex13. TMPyP4 is able to associate and stabilize G-quadruplex, thereby blocking telomerase action. TMPyP4 treatment leads to progressive telomere shortening that eventually results in cancer cell death by apoptosis or senescence14. Because DNA sequence with a potential to form G-quadruplex is widely present on genome, it has been reported that TMPyP4 treatment may lead to multiple consequences including the alteration of expression of particular genes15,16,17,18,19,20 and/or the interference with DNA replication21,22. Therefore, it is important to comprehensively understand biological effects induced by TMPyP4 before it can be used for anti-cancer therapeutics. Moreover, a possible adverse effect is worth investigating. In this report, human A549 cancer cells were treated with TMPyP4 or its derivative TPyP4-Pt (Fig. 1B), and gene expression profile for treated and untreated cells was obtained by RNA-seq. Unexpectedly, we found that among the genes changed by TMPyP4 or TPyP4-Pt, ~27% are involved in cell adhesion and migration, implying that TMPyP4 treatment might affect cancer metastasis. The experiments including cell adhesion assay, scratch-wound healing assay and transwell assay demonstrate that TMPyP4 at commonly used dose (≤0.5 μM, close to its light IC50 values) promotes cancer cell migration. In strikingly contrast, the high-dose of TMPyP4 () inhibits cell proliferation and induces cell death. These findings provide new insights into the complexity of TMPyP4 as a possible anticancer drug.