Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • All components of the UPP were predicted

    2019-08-14

    All components of the UPP were predicted to be susceptible to oxidative stress due to the cysteine residues in their active sites [36]. Curcusone D inhibits DUBs but has no significant effect on the action of E1, E2s, E3s, or the proteasome, which indicates that the targets of the ROS induced by curcusone D have some selectivity. That might be caused by the different sensitivity of proteins to ROS or the preferred binding of curcusone D to particular DUBs. UPP inhibition could cause the accumulation of many proteins that regulate many different pathways involved in cellular apoptosis and cell proliferation. Proteasomal inhibitors could induce the TRAIL apoptotic pathway, activate the JNK pathway, and downregulate the expression of growth-signaling pathway components, including NFκB and the Akt/mTOR pathway [39], [40], [41], [42]. The cytotoxicity induced by the USP7-selective inhibitor P5091 is mediated in part via the HDM2-p21 signaling axis and is independent of p53 [43]. WP1130, an inhibitor of USP9x, USP5, USP14, and UCH37, caused the downregulation of the pro-survival protein Mcl-1, induced aggresome formation, and facilitated apoptosis [44]. We have found that curcusone D could inhibit NFκB reporter luciferase expression and activate the JNK pathway (data not shown). The mechanism of the pathways that are regulated by curcusone D to produce its anti-cancer effects needs to be further elucidated. Peripheral nerve damage is one of the most significant non-hematologic toxicities of bortezomib, which often leads to dose modification and potential changes in the patient\'s treatment plan when it occurs [45]. Other UPP component inhibitors, including a SCFSkp2 E3 inhibitor, act synergistically with bortezomib [7]. Here, we identified that curcusone D combined with bortezomib had synergistic effects on MM cell growth inhibition, cell apoptosis and total ubiquitinated proteins (Fig. 6), which could enhance the potential use of a DUB inhibitor combined with a proteasomal inhibitor. The DUB inhibitor P5091 could induce synergistic anti-MM activity with lenalidomide or Dex amethasone (Dex) [43]. In the future, curcusone D combination therapy to overcome bortezomib resistance or in combination with other clinical agents such as lenalidomide or Dex will be further evaluated. It has been observed that Curcusone D has a strong inhibitory effect against lymphoma and cervical carcinoma 5-aminosalicylic acid manufacturer [46]. Curcusone B, another diterpene isolated from J. curcas, could also effectively suppress cancer cell metastasis [47]. However, the anti-cancer effects and mechanism of curcusone D are still unclear. Here, we have reported for the first time that curcusone D could inhibit the UPP pathway via ROS-induced DUB inhibition, which in terms suppress myeloma cell growth. Curcusone D also induces apoptosis and acts synergistically with bortezomib, which may improve the anti-cancer use of the herbal plant J. curcas. Importantly, the pharmacokinetics and bioavailability of curcusone D and the effective anti-cancer dosages in mouse cancer model need to be evaluated in next stage. The following are the supplementary data related to this article.
    Acknowledgements This work was supported by grants from the National Natural Science Foundation of China (Nos. 91029716, 81072667, and 81125023) and the National Science and Technology Major Projects for “Major New Drugs Innovation and Development” (2012ZX09301001-004). We are grateful to Professor Jian Hou (Chang Zheng Hospital, Shanghai, China) for the presentation of NCI-H929, RPMI 8226, SKO, KM-3, and LP-1 human multiple myeloma (MM) cell lines.
    Introduction DNA damage, oncogenes, and hypoxia are leading causes of cellular damage. In several cellular processes, p53, known as a tumor suppressor protein, has essential roles including roles in cell cycle arrest, DNA repair, angiogenesis, autophagy, migration, aging, senescence, and apoptosis (Fig. 1) [1], [2]. Through these cellular processes, p53 suppresses tumors and has a central role in maintaining genomic stability and preventing the organism from developing diseases such as cancer [3]. Moreover, p53 protects cells from cancer cell proliferation and tumorigenesis by controlling many stress signals [4], [5]. Based on previous reports, mutated p53 is observed in more than 50% of human cancers, indicating that maintenance of the functions of normal p53 is important, as those functions can modulate cell cycle and repair in tumor cells, thereby triggering inhibition of diseases including cancers [6]. In addition, previous studies have indicated that modulation of the ubiquitin-proteasome pathway (UPP) results in regulation of p53 degradation [7], [8]. Several deubiquitinating enzymes (DUBs) target p53 ubiquitination and directly remove ubiquitin chains. Furthermore, some DUBs have been shown to regulate E3 ligases of p53. These DUBs have a vital influence on targeting p53 ubiquitination directly or indirectly (Table 1). DUBs can regulate the p53 signaling pathway via different mechanisms within different cellular compartments in response to different stresses [9]. In eukaryotic cells, most proteins, including p53, are mediated by ubiquitination and deubiquitination pathways. In these pathways, DUBs have key roles in various cellular mechanisms related to homeostasis. Herein, we review the currently available information on p53 ubiquitination and summarize the interaction between various DUBs and p53.