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Suppression of mitochondrial energy production by peptide from photosynthetic bacterial protein inhibits tumor growth

ABSTRACT: Accumulating evidence suggests that bacteria play significant roles in cancer homeostasis. While tumor microbiome has been reevaluated recently, the impact of these bacterial products on tumors has not been widely explored. We previously showed that crosstalk between cancer and P.aeruginosa mediates tumor suppression through bacterial cupredoxin azurin and we designed an azurin-derived peptide. In this study, we identified photosynthetic bacteria/cyanobacteria, such as Chloroflexia, in tumor specimens. Given that Chloroflexus aurantiacus contains at least two cupredoxin genes, we focused on designing novel cell-penetrating peptides derived from the photosynthetic bacterial electron transfer protein auracyanin. Chloroplasts in plants are believed to originate from a cyanobacterial endosymbiont, and some protein characteristics of chloroplasts and mitochondria share commonalities in ATP-dependent energy production. This suggests that such bacterial proteins can alter mitochondrial functions. Consistent with this model, we demonstrated that aurB, a peptide from auracyanin B, localized at mitochondria, blocked their energy production by targeting the gamma subunit of ATP synthase, thereby significantly inhibiting xenografted PC3 tumor growth. More strikingly, aurB in combination with radiation significantly inhibited DU145 tumor volume by 99% at week 5 (vs PBS control, P<0.001) in the tibial bone metastatic model. Reflecting on the anti-tumor effects, the number of metastatic lesions in the lung was significantly reduced (91% reduction vs PBS, P<0.001). A multiplex RNA expression profiling showed that inhibition of ATP production by aurB enhanced the efficacy of radiation by the modulations of multiple pathways through HIF-1α. Collectively, our findings indicate that such electron transfer proteins could represent a significant source of promising novel peptide-based agents for targeting the mitochondrial energy production system that is aberrantly activated in cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285854 | GEO | 2026/01/01

REPOSITORIES: GEO

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Project description:Photosynthetic microbes can produce the clean-burning fuel hydrogen using one of natureâ??s most plentiful resources, sunlight 1,2. Anoxygenic photosynthetic bacteria generate hydrogen and ammonia during a process known as biological nitrogen fixation. This reaction is catalyzed by the enzyme nitrogenase and consumes nitrogen gas, ATP and electrons 3. One bacterium, Rhodopseudomonas palustris, has a remarkable ability to obtain electrons from green plant-derived material 4,5 and to efficiently absorb both high and low intensity light energy to form ATP 6. Manipulating R. palustris or a similar organism to produce hydrogen commercially will require us to identify all its genes that contribute to hydrogen production and to understand how this process is regulated in cells. Here we describe mutant strains in which metabolism is redirected such that hydrogen production is uncoupled from nitrogen fixation. Our data indicate that three different single amino acid changes in the transcriptional regulator NifA each yielded strains that produced hydrogen even in the presence of the repressing nitrogen source ammonium and in the absence of specific inducing metabolic signals. We used the mutants to show that, in addition to nitrogenase genes, 18 genes outside of the nitrogenase gene cluster may contribute to hydrogen production. Some of these genes are likely involved in efficient ATP acquisition and in channeling electrons to nitrogenase for reduction of protons to molecular hydrogen. Our results demonstrate that photosynthetic bacteria can be genetically manipulated for sustained production of pure hydrogen in a variety of cultivation conditions in the absence of oxygen, nitrogen or other gases as long as light and an electron donor are supplied. Transcriptome profile of wild type (CGA009) growing photosynthetically in the presence of amonium an acetate was compare with that of 4 different mutants (CGA570, CGA571, CGA572 and CGA574). We did 2 biological replicates per strain.

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Suppression of mitochondrial energy production by peptide from photosynthetic bacterial protein inhibits tumor growth

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