Browsing by Author "Mathey-Prevot, Bernard"

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    A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer.
    (2011) Curtis, Valerie Forbes
    In many cancer types, infiltration of bone marrow-derived myeloid cells in the tumor microenvironment is often associated with enhanced angiogenesis and tumor progression, resulting in poor prognosis. The polypeptide chemokine PK2 (Bv8) regulates myeloid cell mobilization from the bone marrow, leading to activation of angiogenesis as well as accumulation of macrophages and neutrophils in the tumor site. Neutralizing antibodies against PK2 display potent anti-tumor efficacy, illustrating the potential of PK2-antagonists as therapeutic agents for the treatment of cancer. However, antibody-based therapies can be too large to treat certain diseases and too expensive to manufacture while small molecule therapeutics are not prohibitive in these ways. In this study, we demonstrate the anti-tumor activity of a small molecule PK2 antagonist, PKRA7, in the contexts of glioblastoma and pancreatic cancer xenograft tumor models. In the highly vascularized glioblastoma, PKRA7 decreased blood vessel density while increasing necrotic areas in the tumor mass. Consistent with the anti-angiogenic activity of PKRA7 in vivo, this compound effectively reduced PK2-induced microvascular endothelial cell branching in vitro. For the poorly vascularized pancreatic cancer, the primary anti-tumor effect of PKRA7 is mediated by the blockage of myeloid cell migration and infiltration. At the molecular level, PKRA7 inhibits PK2-induced expression of several pro-migratory chemokines and chemokine receptors in macrophages. Combining PKRA7 treatment with standard chemotherapeutic agents resulted in enhanced effects in xenograft models for both glioblastoma and pancreatic tumors. Taken together, our results indicate that the anti-tumor activity of PKRA7 can be mediated by distinct mechanisms that are relevant to the pathological features of the specific type of cancer. This small molecule PK2 antagonist holds the promise to be further developed as an effective agent for combinational cancer therapy.
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    CoA synthase regulates mitotic fidelity via CBP-mediated acetylation.
    (Nature communications, 2018-03-12) Lin, Chao-Chieh; Kitagawa, Mayumi; Tang, Xiaohu; Hou, Ming-Hsin; Wu, Jianli; Qu, Dan Chen; Srinivas, Vinayaka; Liu, Xiaojing; Thompson, J Will; Mathey-Prevot, Bernard; Yao, Tso-Pang; Lee, Sang Hyun; Chi, Jen-Tsan
    The temporal activation of kinases and timely ubiquitin-mediated degradation is central to faithful mitosis. Here we present evidence that acetylation controlled by Coenzyme A synthase (COASY) and acetyltransferase CBP constitutes a novel mechanism that ensures faithful mitosis. We found that COASY knockdown triggers prolonged mitosis and multinucleation. Acetylome analysis reveals that COASY inactivation leads to hyper-acetylation of proteins associated with mitosis, including CBP and an Aurora A kinase activator, TPX2. During early mitosis, a transient CBP-mediated TPX2 acetylation is associated with TPX2 accumulation and Aurora A activation. The recruitment of COASY inhibits CBP-mediated TPX2 acetylation, promoting TPX2 degradation for mitotic exit. Consistently, we detected a stage-specific COASY-CBP-TPX2 association during mitosis. Remarkably, pharmacological and genetic inactivation of CBP effectively rescued the mitotic defects caused by COASY knockdown. Together, our findings uncover a novel mitotic regulation wherein COASY and CBP coordinate an acetylation network to enforce productive mitosis.
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    Kinome screen of ferroptosis reveals a novel role of ATM in regulating iron metabolism.
    (Cell death and differentiation, 2019-07-18) Chen, Po-Han; Wu, Jianli; Ding, Chien-Kuang Cornelia; Lin, Chao-Chieh; Pan, Samuel; Bossa, Nathan; Xu, Yitong; Yang, Wen-Hsuan; Mathey-Prevot, Bernard; Chi, Jen-Tsan
    Ferroptosis is a specialized iron-dependent cell death that is associated with lethal lipid peroxidation. Modulation of ferroptosis may have therapeutic potential since it has been implicated in various human diseases as well as potential antitumor activities. However, much remains unknown about the underlying mechanisms and genetic determinants of ferroptosis. Given the critical role of kinases in most biological processes and the availability of various kinase inhibitors, we sought to systemically identify kinases essential for ferroptosis. We performed a forward genetic-based kinome screen against ferroptosis in MDA-MB-231 cells triggered by cystine deprivation. This screen identified 34 essential kinases involved in TNFα and NF-kB signaling. Unexpectedly, the DNA damage response serine/threonine kinase ATM (mutated in Ataxia-Telangiectasia) was found to be essential for ferroptosis. The pharmacological or genetic inhibition of ATM consistently rescued multiple cancer cells from ferroptosis triggered by cystine deprivation or erastin. Instead of the canonical DNA damage pathways, ATM inhibition rescued ferroptosis by increasing the expression of iron regulators involved in iron storage (ferritin heavy and light chain, FTH1 and FTL) and export (ferroportin, FPN1). The coordinated changes of these iron regulators during ATM inhibition resulted in a lowering of labile iron and prevented the iron-dependent ferroptosis. Furthermore, we found that ATM inhibition enhanced the nuclear translocation of metal-regulatory transcription factor 1 (MTF1), responsible for regulating expression of Ferritin/FPN1 and ferroptosis protection. Genetic depletion of MTF-1 abolished the regulation of iron-regulatory elements by ATM and resensitized the cells to ferroptosis. Together, we have identified an unexpected ATM-MTF1-Ferritin/FPN1 regulatory axis as novel determinants of ferroptosis through regulating labile iron levels.