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- Cheteh, EH, et al.
(author)
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Interleukin-6 derived from cancer-associated fibroblasts attenuates the p53 response to doxorubicin in prostate cancer cells
- 2020
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In: Cell death discovery. - : Springer Science and Business Media LLC. - 2058-7716. ; 6:1, s. 42-
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Journal article (peer-reviewed)abstract
- Cancer-associated fibroblasts (CAFs) promote tumor growth and progression, and increase drug resistance through several mechanisms. We have investigated the effect of CAFs on the p53 response to doxorubicin in prostate cancer cells. We show that CAFs produce interleukin-6 (IL-6), and that IL-6 attenuates p53 induction and upregulation of the pro-apoptotic p53 target Bax upon treatment with doxorubicin. This is associated with increased levels of MDM2 mRNA, Mdm2 protein bound to p53, and ubiquitinated p53. IL-6 also inhibited doxorubicin-induced cell death. Inhibition of JAK or STAT3 alleviated this effect, indicating that IL-6 attenuates p53 via the JAK/STAT signaling pathway. These results suggest that CAF-derived IL-6 plays an important role in protecting cancer cells from chemotherapy and that inhibition of IL-6 could have significant therapeutic value.
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- Palomar-Siles, M, et al.
(author)
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Translational readthrough of nonsense mutant TP53 by mRNA incorporation of 5-Fluorouridine
- 2022
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In: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 13:11, s. 997-
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Journal article (peer-reviewed)abstract
- TP53 nonsense mutations in cancer produce truncated inactive p53 protein. We show that 5-FU metabolite 5-Fluorouridine (FUr) induces full-length p53 in human tumor cells carrying R213X nonsense mutant TP53. Ribosome profiling visualized translational readthrough at the R213X premature stop codon and demonstrated that FUr-induced readthrough is less permissive for canonical stop codon readthrough compared to aminoglycoside G418. FUr is incorporated into mRNA and can potentially base-pair with guanine, allowing insertion of Arg tRNA at the TP53 R213X UGA premature stop codon and translation of full-length wild-type p53. We confirmed that full-length p53 rescued by FUr triggers tumor cell death by apoptosis. FUr also restored full-length p53 in TP53 R213X mutant human tumor xenografts in vivo. Thus, we demonstrate a novel strategy for therapeutic rescue of nonsense mutant TP53 and suggest that FUr should be explored for treatment of patients with TP53 nonsense mutant tumors.
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- Regan, Robert C., et al.
(author)
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Half-quantum vortices in nematic and chiral phases of 3He
- 2021
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In: Physical Review B. - 2469-9969 .- 2469-9950. ; 104:2
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Journal article (peer-reviewed)abstract
- We report theoretical results for the stability of half-quantum vortices (HQVs) in the superfluid phases of confined in highly anisotropic Nafen aerogel. Superfluidity of confined in Nafen is the realization of a “nematic superfluid” with Cooper pairs condensed into a single -wave orbital aligned along the anisotropy axis of the Nafen aerogel. In addition to the nematic phase, we predict a second “chiral” phase that onsets at a lower transition temperature. This chiral phase spontaneously breaks time-reversal symmetry and is a topological superfluid. Both superfluid phases are equal-spin pairing condensates that host arrays of HQVs as equilibrium states of rotating superfluid . We present results for the structure of HQVs, including magnetic and topological signatures of HQVs in both the nematic and chiral phases of -Nafen.
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- Regan, Robert C., et al.
(author)
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Vortex phase diagram of rotating superfluid He 3 - B
- 2020
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In: Physical Review B. - 2469-9969 .- 2469-9950. ; 101:2
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Journal article (peer-reviewed)abstract
- We present a theoretical calculation of the pressure-temperature-field phase diagram for the vortex phases of rotating superfluid He3-B. Based on a strong-coupling Ginzburg-Landau functional that accounts for the relative stability of the bulk A and B phases of He3 at all pressures, we report calculations for the internal structure and free energies of distinct broken-symmetry vortices in rotating superfluid He3-B. Theoretical results for the equilibrium vortex phase diagram in zero field and an external field of H=284G parallel to the rotation axis, H∥ω, are reported, as well as the supercooling transition line, TV∗(p,H). In zero field the vortex phases of He3-B are separated by a first-order phase transition line TV(p) that terminates on the bulk critical line Tc(p) at a triple point. The low-pressure, low-temperature phase is characterized by an array of singly quantized vortices that spontaneously breaks axial rotation symmetry, exhibits anisotropic vortex currents and an axial current anomaly (D-core phase). The high-pressure, high-temperature phase is characterized by vortices with both bulk A phase and β phase in their cores (A-core phase). We show that this phase is metastable and supercools down to a minimum temperature, TV∗(p,H), below which it is globally unstable to an array of D-core vortices. For H≳60G external magnetic fields aligned along the axis of rotation increase the region of stability of the A-core phase of rotating He3-B, opening a window of stability down to low pressures. These results are compared with the experimentally reported phase transitions in rotating He3-B.
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