Pyruvate kinase M2 regulates homologous recombination-mediated DNA double-strand break repair

Sizemore, Steven T.; Zhang, Manchao; Cho, Ju Hwan; Hurwitz, Brian; Kaur, Balveen; Lehman, Norman L.; Ostrowski, Michael C.; Robe, Pierre A.; Miao, Weili; Wang, Yinsheng; Chakravarti, Arnab; Xia, Fang

doi:10.1038/s41422-018-0086-7

Cited by 57 publications

(56 citation statements)

References 47 publications

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“…We previously reported that PKM2 is upregulated and suggested that it functions as a tumor promoter in human CC [12]. More importantly, it has been found that downregulation of PKM2 effectively enhances radiosensitivity in human non-small-cell lung carcinoma [10, 27] and glioblastoma multiforme cell lines (U87, T98G, and U251) [28]. As anticipated, our results showed that high PKM2 expression was related to clinical radioresistance in patients with CC.…”

Section: Discussionsupporting

confidence: 81%

Knockdown of PKM2 enhances radiosensitivity of cervical cancer cells

et al. 2019

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Background: Pyruvate kinase isozyme type M2 (PKM2) catalyzes the final step in glycolysis and has been found to be up-regulated in multiple human malignancies. However, whether PKM2 regulates the radiosensitivity of human cervical cancer (CC) remains unknown. Methods: The expression of PKM2 in 94 patients with CC in the complete response (CR) and noncomplete response (nCR) groups, was evaluated by immunohistochemistry. The effect of PKM2 inhibition on radiosensitivity, the cell cycle, DNA damage, and apoptosis was evaluated by immunofluorescence analysis, colony formation assay, flow cytometry analysis and Western blotting. Results: PKM2 expression was more highly expressed in the nCR group than that in CR group and PKM2 expression was enhanced in CC cells after ionizing radiation (IR). In addition, knockdown of PKM2 combined with IR significantly reduced cell growth, promoted apoptosis, and enhanced radiosensitivity. Additionally, knockdown of PKM2 with IR resulted in increased phosphorylation of DNA repair checkpoint proteins (ATM) and phosphorylated-H2AX. Moreover, knockdown of PKM2 combined with IR significantly increased the expression of cleaved caspase 3 and caspase 9, whereas Bcl2 expression was suppressed. Furthermore, knockdown of PKM2 combined with IR markedly reduced the expression of several cancer stem cell biomarkers in vitro, including NANOG, OCT4, SOX2, and Bmi1. Conclusions: The results of our study suggests that PKM2 might be involved in mediating CC radiosensitivity and is identified as a potentially important target to enhance radiosensitivity in patients with CC.

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Section: Discussionsupporting

confidence: 81%

Knockdown of PKM2 enhances radiosensitivity of cervical cancer cells

et al. 2019

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“…Pyruvate kinase isoform M2 (PKM2), the key rate-limiting enzyme catalyzing the final step of glycolysis, plays a critical role in tumor glucose metabolism and is highly expressed in various types of human cancers (9,10). PKM2 has been proposed to play a vital role in maintaining the metabolism program (11,12), promoting proliferation (11), resistance to genotoxic treatments (13), and metastasis (14) and inducing cancer stem-like cell properties (15) in many types of cancer. Besides its roles in regulating the cancer cell, PKM2 has been proven to contribute to tumor microenvironment, such as reducing lactate production, increasing OXPHOS (9,16).…”

Section: Introductionmentioning

confidence: 99%

Pyruvate Kinase M2 Promotes Prostate Cancer Metastasis Through Regulating ERK1/2-COX-2 Signaling

Guo

Zhang

et al. 2020

Front. Oncol.

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Pyruvate kinase M2 (PKM2) is a key enzyme of glycolysis, which is highly expressed in many tumor cells, and has emerged as an important player in tumor progression and metastasis. However, the functional roles of PKM2 in tumor metastasis remain elusive. Here we showed that PKM2 promoted prostate cancer metastasis via extracellularregulated protein kinase (ERK)-cyclooxygenase (COX-2) signaling. Based on public databases, we found that PKM2 expression was upregulated in prostate cancer and positively associated with tumor metastasis. Further analysis showed that PKM2 promoted prostate cancer cell migration/invasion and epithelial-mesenchymal transition (EMT) through upregulation of COX-2. Mechanistically, PKM2 interacted with ERK1/2 and regulated its phosphorylation, leading to phosphorylation of transcription factor c-Jun, downstream of ERK1/2, to activate COX-2 transcription by IP and ChIP assay, while inhibition of COX-2 significantly reversed the promotion effect of PKM2 on tumor metastasis in vivo. Taken together, our results suggest that a novel of PKM2-ERK1/2c-Jun-COX-2 axis is a potential target in controlling prostate cancer metastasis.

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“…Some examples of functions of moonlighting proteins secondary to catalysis include signal transduction, transcriptional regulation, apoptosis, motility, and structural functions (31). Cytoplasmic enzymes, pyruvate kinase M2 (PKM2) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH), have acquired secondary non-enzymatic roles such as DNA repair protein in the nucleus and RNA-binding protein (12,30), respectively, in addition to the primary enzyme catalytic roles. These proteins with a glycolysis function have common characteristics to form homo-oligomer and their function and localization were known to differ based on their forms (2,8,25,36).…”

Section: Discussionmentioning

confidence: 99%

<b>Clinicopathological and prognostic significance of nuclear UGDH localization in lung adenocar</b><b>cinoma</b>

et al. 2019

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This study aimed to clarify relationships among UDP-glucose-6 dehydrogenase (UGDH) expression, clinicopathological factors, and the prognosis of patients, and to determine the role of UGDH in lung adenocarcinoma (AC). Firstly, UGDH expression and localization in 126 lung AC tissues were immunohistochemically studied, and associations with clinicopathological parameters and patients' prognosis were evaluated. Secondly, serum UGDH levels were measured in 267 lung cancer patients and 100 healthy controls. Finally, the effects of UGDH knockdown by siRNA on migration and invasion abilities were analyzed. As a result, nuclear UGDH staining was significantly correlated with poorer differentiation, a larger tumor size, higher p-TNM stage, positive nodal metastasis, positive lymphatic invasion, and positive vascular invasion in lung AC patients. Nuclear UGDH-positive patients showed significantly poorer survival than nuclear UGDH-negative patients. Serum UGDH levels were especially higher in lung AC patients even in stage I than those in healthy controls. In lung AC cell lines, nuclear expression levels of UGDH were higher in LC-2/ad cells than in A549 cells. UGDH siRNA-treated LC-2/ad cells showed significantly decreased migration and invasion abilities, but no significant differences were observed in UGDH siRNA-treated A549 cells. These data indicate that UGDH expression and localization are an early sero-diagnostic marker in addition to a poor prognostic indicator in lung AC patients.

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Pyruvate kinase M2 regulates homologous recombination-mediated DNA double-strand break repair

Cited by 57 publications

References 47 publications

Knockdown of PKM2 enhances radiosensitivity of cervical cancer cells

Knockdown of PKM2 enhances radiosensitivity of cervical cancer cells

Pyruvate Kinase M2 Promotes Prostate Cancer Metastasis Through Regulating ERK1/2-COX-2 Signaling

<b>Clinicopathological and prognostic significance of nuclear UGDH localization in lung adenocar</b><b>cinoma</b>

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