RESUMO
The chemotherapeutic drug cisplatin, which targets DNA, serves as one of the main staples in cancer treatment. Yet, the therapeutic application of cisplatin is limited by two major challenges: the occurrence of reversible and irreversible side effects due to non-specific toxicity, and the intrinsic or developing resistance of tumor cells toward cisplatin. Here we demonstrate that cancer cells respond to cisplatin treatment with the nucleolar accumulation of inorganic polyphosphate (polyP), a universally conserved high-energy compound. PolyP accumulation positively correlates with the levels of activated caspase-3, suggesting a novel role of polyP in cisplatin-mediated apoptosis. In support of this finding, we discovered that administration of exogenous polyP increases cisplatin-induced toxicity in select cancer cell lines, raising the exciting possibility that enhancing endogenous polyP levels might be a novel mechanism to sensitize cancer cells to cisplatin treatment.
RESUMO
Polyphosphate (polyP), a several billion-year-old biopolymer, is produced in every cell, tissue, and organism studied. Structurally extremely simple, polyP consists of long chains of covalently linked inorganic phosphate groups. We report here the surprising discovery that polyP shows a remarkable efficacy in accelerating amyloid fibril formation. We found that polyP serves as an effective nucleation source for various different amyloid proteins, ranging from bacterial CsgA to human α-synuclein, Aß1-40/42, and Tau. polyP-associated α-synuclein fibrils show distinct differences in seeding behavior, morphology, and fibril stability compared with fibrils formed in the absence of polyP. In vivo, the amyloid-stimulating and fibril-stabilizing effects of polyP have wide-reaching consequences, increasing the rate of biofilm formation in pathogenic bacteria and mitigating amyloid toxicity in differentiated neuroblastoma cells and C. elegans strains that serve as models for human folding diseases. These results suggest that we have discovered a conserved cytoprotective modifier of amyloidogenic processes.
Assuntos
Peptídeos beta-Amiloides/agonistas , Proteínas de Escherichia coli/agonistas , Fragmentos de Peptídeos/agonistas , Polifosfatos/farmacologia , alfa-Sinucleína/agonistas , Proteínas tau/agonistas , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Geneticamente Modificados , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Linhagem Celular Tumoral , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Expressão Gênica , Humanos , Cinética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Polifosfatos/química , Dobramento de Proteína/efeitos dos fármacos , alfa-Sinucleína/química , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Proteínas tau/química , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
The era in which ROS (reactive oxygen species) were simply the 'bad boys of biology' is clearly over. High levels of ROS are still rightfully considered to be toxic to many cellular processes and, as such, contribute to disease conditions and cell death. However, the high toxicity of ROS is also extremely beneficial, particularly as it is used to kill invading micro-organisms during mammalian host defence. Moreover, a transient, often more localized, increase in ROS levels appears to play a major role in signal transduction processes and positively affects cell growth, development and differentiation. At the heart of all these processes are redox-regulated proteins, which use oxidation-sensitive cysteine residues to control their function and by extension the function of the pathways that they are part of. Our work has contributed to changing the view about ROS through: (i) our characterization of Hsp33 (heat-shock protein 33), one of the first redox-regulated proteins identified, whose function is specifically activated by ROS, (ii) the development of quantitative tools that reveal extensive redox-sensitive processes in bacteria and eukaryotes, and (iii) the discovery of a link between early exposure to oxidants and aging. Our future research programme aims to generate an integrated and system-wide view of the beneficial and deleterious effects of ROS with the central goal to develop more effective antioxidant strategies and more powerful antimicrobial agents.