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Author

Yi Ban

Other affiliations: Rutgers University
Bio: Yi Ban is an academic researcher from University of Medicine and Dentistry of New Jersey. The author has contributed to research in topics: Cancer research & DNA damage. The author has an hindex of 3, co-authored 3 publications receiving 589 citations. Previous affiliations of Yi Ban include Rutgers University.

Papers
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Journal ArticleDOI
TL;DR: It is shown that dexrazoxane specifically abolished the DNA damage signal gamma-H2AX induced by doxorubicin, but not camptothecin or hydrogen peroxide, in H9C2 cardiomyocytes, and this results suggest that dex Razoxane antagonizesDoxorubsicin-induced DNA damage through its interference with Top2beta, which could implicate Top2 beta indoxorUBicin cardiotoxicity.
Abstract: Doxorubicin is among the most effective and widely used anticancer drugs in the clinic. However, cardiotoxicity is one of the life-threatening side effects of doxorubicin-based therapy. Dexrazoxane (Zinecard, also known as ICRF-187) has been used in the clinic as a cardioprotectant against doxorubicin cardiotoxicity. The molecular basis for doxorubicin cardiotoxicity and the cardioprotective effect of dexrazoxane, however, is not fully understood. In the present study, we showed that dexrazoxane specifically abolished the DNA damage signal gamma-H2AX induced by doxorubicin, but not camptothecin or hydrogen peroxide, in H9C2 cardiomyocytes. Doxorubicin-induced DNA damage was also specifically abolished by the proteasome inhibitors bortezomib and MG132 and much reduced in top2beta(-/-) mouse embryonic fibroblasts (MEF) compared with TOP2beta(+/+) MEFs, suggesting the involvement of proteasome and DNA topoisomerase IIbeta (Top2beta). Furthermore, in addition to antagonizing Top2 cleavage complex formation, dexrazoxane also induced rapid degradation of Top2beta, which paralleled the reduction of doxorubicin-induced DNA damage. Together, our results suggest that dexrazoxane antagonizes doxorubicin-induced DNA damage through its interference with Top2beta, which could implicate Top2beta in doxorubicin cardiotoxicity. The specific involvement of proteasome and Top2beta in doxorubicin-induced DNA damage is consistent with a model in which proteasomal processing of doxorubicin-induced Top2beta-DNA covalent complexes exposes the Top2beta-concealed DNA double-strand breaks.

516 citations

Journal ArticleDOI
TL;DR: Results support a model in which Top1 cleavage complexes arrest transcription and activate a ubiquitin-proteasome pathway leading to the degradation of Top1 Cleavage complexes.

94 citations

Journal ArticleDOI
TL;DR: It is shown that the formation of replication-dependent DSBs requires the ubiquitin-proteasome pathway in CPT-treated cells, and results support a replication fork collision model in which Top1 cleavage complexes at the arrested replication forks are degraded by proteasome prior to replication fork runoff on the leading strand to generate D SBs.

67 citations

Journal ArticleDOI
TL;DR: Markowitz et al. as mentioned in this paper showed that deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway activity, leading to generation of an altered differentiation state responsive to PD-1 blockade.
Abstract: Background: TCF1high progenitor CD8+ T cells have been shown to mediate the efficacy of PD-1 checkpoint blockade. However, the mechanisms that govern generation of TCF1high cells are poorly understood. Methods: We sequenced bulk RNA from tumor-infiltrating lymphocytes to identify differentially expressed genes based on tumor progression. We utilized in vitro co-cultures of tumor-specific T cells tumor cells to examine differentiation, effector function, and metabolism of T cells with different genetic and pharmacologic manipulations by flow cytometry, metabolic flux analyses, and metabolomic profiling. We performed in vivo adoptive transfers of control and manipulated tumor-specific T cells into tumor-bearing mice from both a non-small cell lung cancer and a melanoma model to examine effects of genetic manipulation on differentiation and effector function, as well as determine tumor burden and overall mouse survival both in the treatment-naïve and anti-PD-1 treated contexts. Results: RNA Sequencing demonstrated a metabolically active response in tumor-infiltrating CD8+ T cells isolated from large and late-stage tumors. Using a genetic screen targeting glycolytic enzymes up-regulated in tumor-infiltrating CD8+ T cells, we demonstrate that PKM2 deficiency (PKM2KO) enriched for TCF1high progenitor cells. Antigen-specific PKM2KO CD8+ T cells from draining lymph nodes and tumors exhibited a central memory-like phenotype with reduced effector cytokine production, increased CD44/CD62L expression, and increased TCF1 and Eomes in non-small cell lung cancer and melanoma. Adoptive transfer of PKM2KO CD8+ T cells in combination with PD-1 blockade impaired tumor growth and improved survival. PKM2KO CD8+ T cells showed reduced glycolytic flux and accumulation of glycolytic intermediates with concomitant increases in pentose phosphate pathway (PPP) metabolites. Importantly, small molecule agonism of PPP was sufficient to skew activated CD8+ T cells towards the TCF1high population, which combined with PD-1 blockade to impair tumor growth and improve survival. Conclusions: Here we show that targeting glycolytic flux by deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway activity, leading to generation of an altered differentiation state responsive to PD-1 blockade. Our study demonstrates a novel metabolic reprogramming that contributes to a memory-like T cell state amenable to checkpoint blockade. Citation Format: Geoffrey J. Markowitz, Yi Ban, Diamile A. Tavarez, Michael J. Crowley, Liron Yoffe, Mitchell T. Martin, Tito A. Sandoval, Dingcheng Gao, Juan R. Cubillos-Ruiz, Timothy E. McGraw, Nasser K. Altorki, Vivek Mittal. Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway to generate TCF1+ progenitor CD8+ T cells to improve checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 603.
Proceedings ArticleDOI
01 Nov 2022
TL;DR: Siddiqui et al. as discussed by the authors showed that deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway activity, leading to generation of an altered differentiation state responsive to checkpoint blockade.
Abstract:

Background

TCF1high progenitor CD8+ T cells have been shown to mediate the efficacy of PD-1 checkpoint blockade.1-3 However, the mechanisms that govern generation of TCF1high cells are poorly understood.

Methods

We sequenced bulk RNA from tumor-infiltrating lymphocytes to identify differentially expressed genes based on tumor progression. We utilized in vitro co-cultures of tumor-specific T cells tumor cells to examine differentiation, effector function, and metabolism of T cells with different genetic and pharmacologic manipulations by flow cytometry, metabolic flux analyses, and metabolomic profiling. We performed in vivo adoptive transfers of control and genetically manipulated tumor-specific T cells into tumor-bearing mice from both a non-small cell lung cancer and a melanoma model to examine effects of genetic manipulation on differentiation and effector function, as well as determine tumor burden and overall mouse survival both in the treatment-naïve and anti-PD-1 treated contexts.

Results

RNA Sequencing demonstrated a metabolically active response in tumor-infiltrating CD8+ T cells isolated from large and late-stage tumors. Using a genetic screen targeting glycolytic enzymes up-regulated in tumor-infiltrating CD8+ T cells, we demonstrate that PKM2 deficiency (PKM2KO) enriched for TCF1high progenitor cells (figure 1). Antigen-specific PKM2KO CD8+ T cells from draining lymph nodes and tumors exhibited a central memory-like phenotype (figure 2) with reduced effector cytokine production, increased CD44/CD62L expression, and increased TCF1 and Eomes in non-small cell lung cancer and melanoma. Adoptive transfer of PKM2KO CD8+ T cells in combination with PD-1 blockade impaired tumor growth and improved survival (figure 3). PKM2KO CD8+ T cells showed reduced glycolytic flux and accumulation of glycolytic intermediates with concomitant increases in pentose phosphate pathway (PPP) metabolites. Importantly, small molecule agonism of PPP was sufficient to skew activated CD8+ T cells towards the TCF1high population (figure 4).

Conclusions

Here we show that targeting glycolytic flux by deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway activity, leading to generation of an altered differentiation state responsive to PD-1 blockade. Our study demonstrates a novel metabolic reprogramming that contributes to a memory-like T cell state amenable to checkpoint blockade.

Acknowledgements

This work was supported by NIH grants T32 CA203702 and KL2-TR-002385 to GJM, and funds from the Neuberger Berman Foundation Lung Cancer Research Center to NKA and VM.

References

Escobar G, Mangani D & Anderson AC. T cell factor 1: A master regulator of the T cell response in disease. Sci Immunol 2020;5. Siddiqui I, et al. I Intratumoral Tcf1 + PD-1 + CD8 + T Cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 2019;50:195–211.e110. Kurtulus S, et al. Checkpoint blockade immunotherapy induces dynamic changes in PD-1-CD8+ Tumor-Infiltrating T Cells. Immunity 2019;50:181–194.e186. Luckey CJ, et al. Memory T and memory B cells share a transcriptional program of self-renewal with long-term hematopoietic stem cells. Proc Natl Acad Sci USA Feb 2006;28:103(9):3304–9.

Ethics Approval

All animal work was performed in accordance with an animal protocol approved by the institutional Animal Care and Use Committee at Weill Cornell Medical College (Protocol number 0806-762A).

Cited by
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Journal ArticleDOI
TL;DR: This review focuses on the molecular and biochemical characteristics of topoisomerases and their inhibitors and discusses the common mechanism of action ofTopoisomerase poisons by interfacial inhibition and trapping of topisomerase cleavage complexes.

1,587 citations

Journal ArticleDOI
TL;DR: These studies promise refined targeting of TOP2 as an effective anticancer strategy and the ability to interfere with TOP2 and generate enzyme-mediated DNA damage is an effective strategy for cancer chemotherapy.
Abstract: Recent molecular studies have expanded the biological contexts in which topoisomerase II (TOP2) has crucial functions, including DNA replication, transcription and chromosome segregation. Although the biological functions of TOP2 are important for ensuring genomic integrity, the ability to interfere with TOP2 and generate enzyme-mediated DNA damage is an effective strategy for cancer chemotherapy. The molecular tools that have allowed an understanding of the biological functions of TOP2 are also being applied to understanding the details of drug action. These studies promise refined targeting of TOP2 as an effective anticancer strategy.

1,466 citations

Journal ArticleDOI
TL;DR: Cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation.
Abstract: Doxorubicin is believed to cause dose-dependent cardiotoxicity through redox cycling and the generation of reactive oxygen species (ROS). Here we show that cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure, suggesting that doxorubicin-induced cardiotoxicity is mediated by topoisomerase-IIβ in cardiomyocytes.

1,424 citations

Journal ArticleDOI
TL;DR: A brief background on the literature supporting the PharmGKB pathway about doxorubicin action, and a summary of this active area of research can be found in this paper.
Abstract: The goal of this study is to give a brief background on the literature supporting the PharmGKB pathway about doxorubicin action, and provides a summary of this active area of research. The reader is referred to recent in-depth reviews [1–4] for more detailed discussion of this important and complex pathway. Doxorubicin is an anthracyline drug first extracted from Streptomyces peucetius var. caesius in the 1970’s and routinely used in the treatment of several cancers including breast, lung, gastric, ovarian, thyroid, non-Hodgkin’s and Hodgkin’s lymphoma, multiple myeloma, sarcoma, and pediatric cancers [5–7]. A major limitation for the use of doxorubicin is cardiotoxicity, with the total cumulative dose being the only criteria currently used to predict the toxicity [4,8]. As there is evidence that the mechanisms of anticancer action and of cardiotoxicity occur through different pathways there is hope for the development of anthracycline drugs with equal efficacy but reduced toxicity [4]. Knowledge of the pharmacogenomics of these pathways may eventually allow for future selection of patients more likely to achieve efficacy at lower doses or able to withstand higher doses with lesser toxicity. We present here graphical representations of the candidate genes for the pharmacogenomics of doxorubicin action in a stylized cancer cell (Fig. 1) and toxicity in cardiomyocytes (Fig. 2), and a table describing the key variants examined so far. Open in a separate window Fig. 1 Graphical representation of the candidate genes involved in the pharmacodynamics of doxorubicin in a stylized cancer cell. A fully interactive version of this pathway is available online at PharmGKB at http://www.pharmgkb.org/do/serve?objId=PA165292163o ROS, reactive oxygen species.

1,168 citations

Journal ArticleDOI
TL;DR: The incidence of cardiotoxicity caused by commonly used chemotherapeutic agents as well as the pathogenesis, diagnosis, management, and prevention of these cardiovascular side effects are reviewed.

1,080 citations