Suppression of mitochondrial energy production by a photosynthetic bacterial cupredoxin peptide inhibits tumor growth

Accumulating evidence shows that bacteria influence cancer homeostasis, yet the effects of tumor‑associated microbes and their products remain largely unexplored. We previously reported that P. aeruginosa-cancer crosstalk suppresses tumors via the bacterial cupredoxin azurin, and we developed an azurin‑derived peptide that was tested in clinical trials. Building on our previous studies, we studied tumor-resident bacteria for novel therapeutics and targets. Photosynthetic bacteria from the phylum Chloroflexota, including a member of the class Chloroflexia, identified in tumors, carry the cupredoxin auracyanin gene. Based on the structural and chemical characteristics of auracyanin, we designed a novel cell-penetrating peptide, aurB. Plant chloroplasts are thought to have evolved from a bacterial endosymbiont, and both chloroplasts and mitochondria possess shared proteins essential for ATP-dependent energy production, indicating that these bacterial-derived proteins may influence mitochondrial function. Consistent with this model, we demonstrated that aurB, a peptide from cupredoxin auracyanin B, localized at mitochondria, blocked energy production by targeting ATP synthase in prostate cancer cells, thereby significantly inhibiting tumor growth. More strikingly, combination treatment with aurB and radiation therapy significantly inhibited tumor growth in a tibial bone metastasis model. Moreover, the number of metastatic lesions in the lungs was also significantly lower upon aurB treatment. Multiplex RNA-expression profiling revealed that the inhibition of ATP production by aurB increased the efficacy of radiation therapy by modulating multiple pathways involving HIF-1α. Our findings indicate that electron transfer proteins could represent an important source of promising novel peptide-based agents that target the aberrantly activated mitochondrial energy system in cancer.