Dataset Information

Accumulation of Nucleolar Inorganic Polyphosphate Is a Cellular Response to Cisplatin-Induced Apoptosis.

ABSTRACT: 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.

SUBMITTER: Xie L

PROVIDER: S-EPMC6920253 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Accumulation of Nucleolar Inorganic Polyphosphate Is a Cellular Response to Cisplatin-Induced Apoptosis.

Xie Lihan L Rajpurkar Asavari A Quarles Ellen E Taube Nicole N Rai Akash S AS Erba Jake J Sliwinski Benjamin B Markowitz Moses M Jakob Ursula U Knoefler Daniela D

Frontiers in oncology 20191212

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 uni ...[more]

PMID: 31921667

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Project description:Bacteria synthesize inorganic polyphosphate (polyP) in response to a variety of different stress conditions. polyP protects bacteria by acting as a protein-stabilizing chaperone, metal chelator, or regulator of protein function, among other mechanisms. However, little is known about how stress signals are transmitted in the cell to lead to increased polyP accumulation. Previous work in the model enterobacterium Escherichia coli has indicated that the RNA polymerase-binding regulatory protein DksA is required for polyP synthesis in response to nutrient limitation stress. In this work, I set out to characterize the role of DksA in polyP regulation in more detail. I found that overexpression of DksA increases cellular polyP content (explaining the long-mysterious phenotype of dksA overexpression rescuing growth of a dnaK mutant at high temperatures) and characterized the roles of known functional residues of DksA in this process, finding that binding to RNA polymerase is required but that none of the other functions of DksA appear to be necessary. Transcriptomics revealed genome-wide transcriptional changes upon nutrient limitation, many of which were affected by DksA, and follow-up experiments identified complex interactions between DksA and the stress-sensing alternative sigma factors FliA, RpoN, and RpoE that impact polyP production, indicating that regulation of polyP synthesis is deeply entwined in the multifactorial stress response network of E. coliIMPORTANCE Inorganic polyphosphate (polyP) is an evolutionarily ancient, widely conserved biopolymer required for stress resistance and pathogenesis in diverse bacteria, but we do not understand how its synthesis is regulated. In this work, I gained new insights into this process by characterizing the role of the transcriptional regulator DksA in polyP regulation in Escherichia coli and identifying previously unknown links between polyP synthesis and the stress-responsive alternative sigma factors FliA, RpoN, and RpoE.

Dataset Information

Accumulation of Nucleolar Inorganic Polyphosphate Is a Cellular Response to Cisplatin-Induced Apoptosis.

Publications

Accumulation of Nucleolar Inorganic Polyphosphate Is a Cellular Response to Cisplatin-Induced Apoptosis.

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