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
  • br Promotion of GLS expression Glutamine metabolism is anoth

    2021-09-18


    Promotion of GLS2 expression Glutamine metabolism is another target for alteration in ferroptosis. Glutamine is required for the induction of ferroptosis during serum-induced injury after amino Erastin australia starvation [72]. The first step of glutamine catabolism is its conversion to glutamate, which is catalyzed by cytosolic glutamine amidotransferases or by mitochondrial glutaminases [73]. Glutamate can be further converted into α-ketoglutarate, which is an important substrate for the citric acid cycle to produce ATP in the mitochondria [73]. As a core member of the mitochondrial glutaminases, GSL2 (glutaminase 2) has been recently identified as a transcriptional target of p53 and its expression is responsible for p53-mediated oxygen consumption, mitochondrial respiration, and ATP generation in cancer cells [74]. Moreover, GLS2 expression increases cellular antioxidant function through increased GSH production in HepG2, HCT116 (a human colorectal cancer cell line), and LN-2024 (a human glioblastoma cell line) cells [74]. Based on these findings [74], GLS2 should be a negative regulator of ferroptosis. However, a recent study observed that knockdown of GLS2 inhibits (but not promotes) serum-dependent ferroptosis in fibroblasts (Fig. 1) through control of glutaminolysis [72]. Whether the specific requirement of GLS2 in erastin- or RSL3-induced ferroptosis and whether GLS2 is responsible for p53-induced ferroptosis requires further investigation.
    Pro-survival function of p53 in ferroptosis
    Promotion of CDKN1A/p21 expression The tumor suppressor CDKN1A/p21 (cyclin dependent kinase inhibitor 1A, also known as p21WAF1/Cip1) is a key mediator of p53-dependent cell cycle arrest after DNA damage [75]. CDKN1A also has pro-survival functions in response to oxidative stress by inhibiting apoptosis. A recent study reports that p53-mediated CDKN1A expression delays the onset of ferroptosis in response to subsequent cystine deprivation in cancer cells (Fig. 1) [11]. Increased p53 expression by using the MDM2 inhibitor nutlin-3 blocks system xc− inhibitor-induced ferroptosis in HT-1080 cells [11]. In contrast, CRISPR/Cas9 technology-mediated p53 depletion cells are sensitive to ferroptosis [11], supporting a pro-survival function of p53 in ferroptosis. This reduced sensitivity to ferroptosis in wild type p53 cells requires p53-dependent expression of CDKN1A and subsequently, the production of intracellular GSH [11]. CDKN1A mediates its activities in cell cycle arrest, primarily by binding to and inhibiting the kinase activity of the cyclin-dependent kinases (CDKs) [75]. Interestingly, CDKN1A-mediated cell cycle arrest is not enough to inhibit ferroptosis since CDK4/6 inhibitors cannot block ferroptosis [11]. Understanding the mechanism of action of CDKN1A in ferroptosis may shed new light on the role of CDKN1A in the development and treatment of cancer.
    Conclusions and perspectives It is clear that systemic or local iron overload can cause various pathological conditions and disease such as hemochromatosis [76], [77], [78]. Excess iron can be a risk for carcinogenesis and neurodegenerative diseases [79], [80]. However, the mechanism responsible for cell death in response to iron overload is not fully understood. Ferroptosis seems to be a unique form of the cell death pathway linked to iron overload, in accordance with its name. The original study indicated that ferroptosis is different from other types of regulated cell death including apoptosis, necroptosis, and autophagy [15]. However, this notion has been challenged by recent studies. For example, erastin can induce CASP9/Caspase 9-dependent mitochondrial apoptosis in cancer cells [29]. Necroptosis-deficient cells seem more sensitive to ferroptosis [81]. In addition, the activation of autophagy appears to be a universal event among the induction of ferroptosis [57], [58]. The molecular mechanism in ferroptosis is more complex than previously thought [17], [18]. Indeed, these so-called core regulators of ferroptosis such as SLC7A11, GPX4, ACSL4, NFE2L2, and p53 have been engaged in the control of other types of regulated cell death. Unfortunately, the unique effector in the network of ferroptosis remains unknown and needs to be identified. The bidirectional control of ferroptosis by p53 through transcription-dependent and -independent mechanisms is context-dependent [11], [12], [13], [14]. Furthermore, p53 is a multifunctional protein with multiple potential modifications and biochemical properties from the regulation by single-nucleotide polymorphism, long non-coding RNAs, and SOCS1 (suppressor of cytokine signaling 1) in ferroptosis [82], [83], [84], [85], [86]. Although the molecular switch between apoptosis and ferroptosis in p53-mediated cell death are poorly understood, certain Bcl-2 family members such as BID (BH3 interacting domain death agonist) and BBC3/PUMA may play a role in the regulation of the crosstalk between these two types of cell death through induction of mitochondrial metabolism or ER stress [36], [87]. A better understanding of the mechanisms by which p53 controls ferroptosis in cancer and non-cancer cells could allow us to develop new treatments for human diseases.