Archives

  • 2018-07
  • 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
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • br Implications for cancer ROS have a long history of

    2024-01-22


    Implications for cancer ROS have a long history of being involved in the development and progression of cancer and increased ROS level is considered as a hallmark of many tumors [76], [77]. Initially, it was thought that ROS would serve as chemical mutagens that would indiscriminately damage cellular macromolecules such as DNA by oxidative stress, and thus are tumorigenic by promoting genomic instability. In addition, the more recent findings that ROS, most notably H2O2, can also mediate several signaling processes in the cell with very specific oxidation targets has verified this view (recently reviewed in [78]). By regulating signaling events that control the cell proliferation rate, alter the metabolic states of the cell and promote angiogenesis, ROS are increasing the tumorigenic potential of the cancerous cells. Increased ROS production in cancer lomitapide sale can be due to multiple different factors. Oncogenes such as Ras promote the generation of ROS [79], [80], [81], [82]. The tumor suppressor p53 is known to establish the redox balance by regulating the expression of antioxidants like GPx1 and SOD2, and loss in its activity can increase the oxidative burden in tumor cells [83], [84], [85]. Increased metabolism of the tumor cells is another factor that increases the ROS levels in these cells (reviewed in [77]). Many human tumors and cultured tumor cell lines show an upregulation of the mRNA expression and/or protein levels of several different NOX enzymes, which are implicated in increasing the cellular ROS levels. Depending on the subcellular localization of these enzymes and the stage of tumorigenesis, NOX-derived ROS can mediate DNA damage causing genomic instability or signal to activate redox-sensitive pathways, to help in initiation and maintenance of tumorigenesis [86], [87]. Along with this, a wide variety of human tumors harbor mutations in mitochondrial DNA-encoding ETC proteins, which are responsible for increasing the mitochondrial-derived ROS production [88]. NOX enzymes can regulate the MAPK/ERK and PI3K/Akt/mTOR signaling pathways through H2O2-mediated oxidation of phosphatases involved in these processes [89], [90], [91]. PTEN is the primary target of H2O2, and oxidation of its active site cysteine (Cys124) inactivates the phosphatase, resulting in constitutive activation of the PI3K pathway [89]. Inactivation of protein phosphatase 2A (PP2A) and PTP1B by H2O2-mediated oxidation causes an increase in Akt activation. This leads to an increased cell proliferation response, anchorage-independent growth and survival [90], [92], [93]. Mitochondrial ROS are also responsible to activate the hypoxia-inducible factors (HIFs) in hypoxic tumor cells, thus allowing the tumor cells to adapt to the low oxygen microenvironment and help in its survival. Under hypoxic conditions, increased superoxide generated by mitochondrial ETC stabilizes HIF-1α and HIF-2α subunits [94], [95]. It has also been reported that AiP is involved in the etiology of human cancer ([96], [97], [98], [99], [100], [101], [102], [103], [104], [105], [106]; recently reviewed in [18]). Chemo- and radiotherapy of human patients often aims to induce the death of the tumor cells. However, apoptotic tumor cells in return may generate signals for AiP and despite initial tumor regression, the tumor cells repopulate and the tumor grows back [97], [98], [99], [102]. Although a direct role of ROS for this type of tumor AiP has not been demonstrated so far, based on the work in several model organisms, it is possible that this is the case. Future work will need to address this question. ROS have not only a tumor-promoting role, but they can also have a tumor-suppressive function. For example, genetically engineered mice carrying oncogenic K-Ras and B-Raf mutations significantly increased tumor development and mortality upon dietary supplementation of the anti-oxidants N-acetylcysteine (NAC) or Vitamin E, suggesting that ROS prevented tumor growth in these animals [107]. Thus, for the application of therapies which potentially target ROS, we need to have a very detailed context-specific understanding of the role of ROS in these tumors. That will be a challenge for the future.