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      Cinobufacini injection suppresses the proliferation of human osteosarcoma cells by inhibiting PIN1-YAP/TAZ signaling pathway

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          Abstract

          Cinobufacini injection (CI), an aqueous extract of Cutis Bufonis, is clinically used for cancer therapy in China, but its molecular mechanism for the treatment of osteosarcoma (OS) remains unclear. We constructed U2OS ectopic subcutaneous tumor model to verify the anti-OS effect of CI in vivo. Meanwhile, cell proliferation of U2OS and MG63 cells was monitored in vitro using the CCK-8 assay, colony formation and morphological changes. Cell cycle arrest and apoptosis were detected by flow cytometry and western blot, which showed that CI significantly inhibited proliferation, induced cell cycle arrest and apoptosis in human OS cells. The further RNA-seq results identified that the Hippo signaling pathway was involved in the anti-OS effect of CI. YAP/TAZ are two major components of the Hippo pathway in breast cancer and are positively regulated by prolyl isomerase PIN1, we assessed their role in OS using both clinicopathological sections and western blots. CI also inhibited PIN1 enzyme activity in a dose-dependent manner, which resulted in impaired PIN1, YAP, and TAZ expression in vitro and in vivo. Additionally, 15 potential compounds of CI were found to occupy the PIN1 kinase domain and inhibit its activity. In summary, CI plays an anti-OS role by down-regulating the PIN1-YAP/TAZ pathway.

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          Most cited references53

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          Proliferation, cell cycle and apoptosis in cancer.

          Beneath the complexity and idiopathy of every cancer lies a limited number of 'mission critical' events that have propelled the tumour cell and its progeny into uncontrolled expansion and invasion. One of these is deregulated cell proliferation, which, together with the obligate compensatory suppression of apoptosis needed to support it, provides a minimal 'platform' necessary to support further neoplastic progression. Adroit targeting of these critical events should have potent and specific therapeutic consequences.
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            Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth.

            YAP/TAZ are nuclear effectors of the Hippo pathway regulating organ growth and tumorigenesis. Yet, their function as transcriptional regulators remains underinvestigated. By ChIP-seq analyses in breast cancer cells, we discovered that the YAP/TAZ transcriptional response is pervasively mediated by a dual element: TEAD factors, through which YAP/TAZ bind to DNA, co-occupying chromatin with activator protein-1 (AP-1, dimer of JUN and FOS proteins) at composite cis-regulatory elements harbouring both TEAD and AP-1 motifs. YAP/TAZ/TEAD and AP-1 form a complex that synergistically activates target genes directly involved in the control of S-phase entry and mitosis. This control occurs almost exclusively from distal enhancers that contact target promoters through chromatin looping. YAP/TAZ-induced oncogenic growth is strongly enhanced by gain of AP-1 and severely blunted by its loss. Conversely, AP-1-promoted skin tumorigenesis is prevented in YAP/TAZ conditional knockout mice. This work highlights a new layer of signalling integration, feeding on YAP/TAZ function at the chromatin level.
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              The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease.

              Protein phosphorylation regulates many cellular processes by causing changes in protein conformation. The prolyl isomerase PIN1 has been identified as a regulator of phosphorylation signalling that catalyses the conversion of specific phosphorylated motifs between the two completely distinct conformations in a subset of proteins. PIN1 regulates diverse cellular processes, including growth-signal responses, cell-cycle progression, cellular stress responses, neuronal function and immune responses. In line with the diverse physiological roles of PIN1, it has also been linked to several diseases that include cancer, Alzheimer's disease and asthma, and thus it might represent a novel therapeutic target.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                17 March 2023
                2023
                : 14
                : 1081363
                Affiliations
                [1] 1 School of Integrative Medicine , Tianjin University of Traditional Chinese Medicine , Tianjin, China
                [2] 2 State Key Laboratory of Component-Based Chinese Medicine , Tianjin, China
                [3] 3 Department of Joint Surgery , Tianjin Hospital , Tianjin University , Tianjin, China
                [4] 4 Department of Spinal Surgery , Tianjin Hospital , Tianjin University , Tianjin, China
                Author notes

                Edited by: Jing Pan, Houston Methodist Research Institute, United States

                Reviewed by: Ajantha Sinniah, University of Malaya, Malaysia

                John Lamar, Albany Medical College, United States

                *Correspondence: Liming Song, sososlm@ 123456126.com ; Changbao Chen, Abosse_chen@ 123456163.com ; Yu Wang, wangyanyan@ 123456tjutcm.edu.cn
                [ † ]

                These authors have contributed equally to this work

                This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Pharmacology

                Article
                1081363
                10.3389/fphar.2023.1081363
                10063998
                bb153ef7-a69d-46a2-87fb-f64692ea3ff7
                Copyright © 2023 Chen, Wang, Zhai, Yuan, Wang, Jin, Dang, Song, Chen and Wang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 27 October 2022
                : 08 March 2023
                Funding
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                This work was supported by the National Natural Science Foundation (No. 82004092, China) and TianJin Youth Medicine Talents Plan, 2020 Annual Graduate Students Innovation Fund, School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China (No. ZXYCXLX202005) and Tianjin Applied Basic Research Diversified Investment Foundation (Grant No. 21JCYBJC01100). The CI was provided by Anhui Jinchan Biochemistry Sharers Co., a subsidiary of China Resource Sanjiu Medical Pharmaceutical Co., Ltd.
                Categories
                Pharmacology
                Original Research

                Pharmacology & Pharmaceutical medicine
                cinobufacini injection,osteosarcoma,pin1,yap,taz
                Pharmacology & Pharmaceutical medicine
                cinobufacini injection, osteosarcoma, pin1, yap, taz

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