137
Views
0
CrossRef citations to date
0
Altmetric
Review

Restoration of p53 Functions By Suppression of mortalin–p53 Sequestration: an Emerging Target in Cancer Therapy

ORCID Icon, ORCID Icon, ORCID Icon, ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon show all
Pages 2087-2112 | Received 28 Feb 2023, Accepted 30 Aug 2023, Published online: 25 Oct 2023

References

  • WHO . Cancer (2022). www.who.int/news-room/fact-sheets/detail/cancer
  • Ando K , OkiE, ZhaoYet al. Mortalin is a prognostic factor of gastric cancer with normal p53 function. Gastric Cancer17(2), 255–262 (2014).
  • Niazi S , PurohitM, NiaziJH. Role of p53 circuitry in tumorigenesis: a brief review. Eur. J. Med. Chem.158, 7–24 (2018).
  • Lu WJ , LeeNP, KaulSCet al. Mortalin–p53 interaction in cancer cells is stress dependent and constitutes a selective target for cancer therapy. Cell Death Diff.18(6), 1046–1056 (2011).
  • Moseng MA , NixJC, PageRC. 2- and N6-functionalized adenosine-5′-diphosphate analogs for the inhibition of mortalin. FEBS Lett.593(15), 2030–2039 (2019).
  • Furet P , MasuyaK, KallenJet al. Discovery of a novel class of highly potent inhibitors of the p53–MDM2 interaction by structure-based design starting from a conformational argument. Bioorg. Med. Chem. Lett.26(19), 4837–4841 (2016).
  • Wadhwa R , TakanoS, KaurKet al. Upregulation of mortalin/mthsp70/Grp75 contributes to human carcinogenesis. Int. J. Cancer118(12), 2973–2980 (2006).
  • Tai-Nagara I , MatsuokaS, ArigaH, SudaT. Mortalin and DJ-1 coordinately regulate hematopoietic stem cell function through the control of oxidative stress. Blood123(1), 41–50 (2014).
  • Kanai M , MaZ, IzumiHet al. Physical and functional interaction between mortalin and Mps1 kinase. Genes Cells12(6), 797–810 (2007).
  • Wadhwa R , YaguchiT, HasanMK, TairaK, KaulSC. Mortalin–MPD (mevalonate pyrophosphate decarboxylase) interactions and their role in control of cellular proliferation. Biochem. Biophys. Res. Commun.302(4), 735–742 (2003).
  • Chen J , LiuWB, JiaWDet al. Overexpression of mortalin in hepatocellular carcinoma and its relationship with angiogenesis and epithelial to mesenchymal transition. Int. J. Oncol.44(1), 247–255 (2014).
  • Ryu J , KaulZ, YoonARet al. Identification and functional characterization of nuclear mortalin in human carcinogenesis. J. Biol. Chem.289(36), 24832–24844 (2014).
  • Daniele S , SestitoS, PietrobonoDet al. Dual inhibition of PDK1 and aurora kinase a: an effective strategy to induce differentiation and apoptosis of human glioblastoma multiforme stem cells. ACS Chem. Neurosci.8(1), 100–114 (2017).
  • Yang L , GuoW, ZhangQet al. Crosstalk between Raf/MEK/ERK and PI3K/AKT in suppression of Bax conformational change by Grp75 under glucose deprivation conditions. J. Mol. Biol.414(5), 654–666 (2011).
  • Cui X , LiZ, PiaoJet al. Mortalin expression in pancreatic cancer and its clinical and prognostic significance. Hum. Pathol.64, 171–178 (2017).
  • Na Y , KaulSC, RyuJet al. Stress chaperone mortalin contributes to epithelial-to-mesenchymal transition and cancer metastasis. Cancer Res.76(9), 2754–2765 (2016).
  • Kussie PH , GorinaS, MarechalVet al. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science274(5289), 948–953 (1996).
  • Popowicz GM , CzarnaA, HolakTA. Structure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain. Cell Cycle7(15), 2441–2443 (2008).
  • Bochkareva E , KaustovL, AyedAet al. Single-stranded DNA mimicry in the p53 transactivation domain interaction with replication protein A. Proc. Natl Acad. Sci. USA102(43), 15412–15417 (2005).
  • Baptiste N , FriedlanderP, ChenX, PrivesC. The proline-rich domain of p53 is required for cooperation with anti-neoplastic agents to promote apoptosis of tumor cells. Oncogene21(1), 9–21 (2002).
  • Wang Y , RosengarthA, LueckeH. Structure of the human p53 core domain in the absence of DNA. Acta Crystallogr. Sect. D63(3), 276–281 (2007).
  • Cho Y , GorinaS, JeffreyPD, PavletichNP. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science265(5170), 346–355 (1994).
  • Pérez Cañadillas JM , TidowH, FreundSMV, RutherfordTJ, AngHC, FershtAR. Solution structure of p53 core domain: structural basis for its instability. Proc. Natl Acad. Sci. USA103(7), 2109–2114 (2006).
  • Ho WC , FitzgeraldMX, MarmorsteinR. Structure of the p53 core domain dimer bound to DNA. J. Biol. Chem.281(29), 20494–20502 (2006).
  • Kitayner M , RozenbergH, KesslerNet al. Structural basis of DNA recognition by p53 tetramers. Mol. Cell22(6), 741–753 (2006).
  • Joerger AC , FershtAR. The tumor suppressor p53: from structures to drug discovery. Cold Spring Harb. Perspect. Biol.2(6), doi: 10.1101/cshperspect.a000919 (2010).
  • Stommel JM , MarchenkoND, JimenezGS, MollUM, HopeTJ, WahlGM. A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking. EMBO J.18(6), 1660–1672 (1999).
  • Tidow H , MeleroR, MylonasEet al. Quaternary structures of tumor suppressor p53 and a specific p53-DNA complex. Proc. Natl Acad. Sci. USA104(30), 12324–12329 (2007).
  • Wells M , TidowH, RutherfordTJet al. Structure of tumor suppressor p53 and its intrinsically disordered N-terminal transactivation domain. Proc. Natl Acad. Sci. USA105(15), 5762–5767 (2008).
  • Ramraj SK , ElayapillaiSP, PelikanRCet al. Novel ovarian cancer maintenance therapy targeted at mortalin and mutant p53. Int. J. Cancer147(4), 1086–1097 (2020).
  • Zhu G , PanC, BeiJXet al. Mutant p53 in cancer progression and targeted therapies. Front. Oncol.10(November), 1–9 (2020).
  • Boutelle AM , AttardiLD. p53 and tumor suppression: it takes a network. Trends Cell Biol.31(4), 298–310 (2021).
  • Aubrey BJ , KellyGL, JanicA, HeroldMJ, StrasserA. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression?Cell Death Diff.25(1), 104–113 (2017).
  • Kruiswijk F , LabuschagneCF, VousdenKH. p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat. Rev. Mol. Cell Biol.16(7), 393–405 (2015).
  • Lacroix M , RiscalR, ArenaG, LinaresLK, LeCam L. Metabolic functions of the tumor suppressor p53: implications in normal physiology, metabolic disorders, and cancer. Mol. Metab.33, 2–22 (2020).
  • Moon SH , HuangCH, HoulihanSLet al. p53 represses the mevalonate pathway to mediate tumor suppression. Cell176(3), 564–580 (2019).
  • Jiang L , KonN, LiTet al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature520(7545), 57–62 (2015).
  • Ou Y , WangSJ, LiD, ChuB, GuW. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc. Natl Acad. Sci. USA113(44), E6806–E6812 (2016).
  • Kim NH , KimHS, LiXYet al. A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial–mesenchymal transition. J. Cell Biol.195(3), 417–433 (2011).
  • Wang SP , WangWL, ChangYLet al. p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nat. Cell Biol.11(6), 694–704 (2009).
  • Chang CJ , ChaoCH, XiaWet al. p53 regulates epithelial–mesenchymal transition and stem cell properties through modulating miRNAs. Nat. Cell Biol.13(3), 317–323 (2011).
  • Assadian S , El-AssaadW, WangXQDet al. p53 inhibits angiogenesis by inducing the production of arresten. Cancer Res.72(5), 1270–1279 (2012).
  • Teodoro JG , EvansSK, GreenMR. Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome. J. Mol. Med.85(11), 1175–1186 (2007).
  • Ho T , TanBX, LaneD. How the other half lives: what p53 does when it is not being a transcription factor. Int. J. Mol. Sci.21(1), 1–19 (2019).
  • Kadosh E , Snir-AlkalayI, VenkatachalamAet al. The gut microbiome switches mutant p53 from tumour-suppressive to oncogenic. Nature586(7827), 133–138 (2020).
  • Pan M , BlattnerC. Regulation of p53 by E3s. Cancers (Basel)13(4), 745 (2021).
  • Vijayakumaran R , TanKH, MirandaPJ, HauptS, HauptY. Regulation of mutant p53 protein expression. Front. Oncol.5(Dec), 3–10 (2015).
  • Boehme KA , KulikovR, BlattnerC. p53 stabilization in response to DNA damage requires Akt/PKB and DNA-PK. Proc. Natl Acad. Sci. USA105(22), 7785–7790 (2008).
  • Carr MI , JonesSN. Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis. Transl. Cancer Res.5(6), 707–724 (2016).
  • Zindy F , EischenCM, RandleDHet al. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev.12(15), 2424–2433 (1998).
  • Zhou X , CaoB, LuH. Negative auto-regulators trap p53 in their web. J. Mol. Cell Biol.9(1), 62–68 (2017).
  • Yu H , YueX, ZhaoYet al. LIF negatively regulates tumour-suppressor p53 through Stat3/ID1/MDM2 in colorectal cancers. Nat. Commun.5(1), 1–12 (2014).
  • Krzeszinski JY , ChoeV, ShaoJet al. XPC promotes MDM2-mediated degradation of the p53 tumor suppressor. Mol. Biol. Cell25(2), 213–221 (2014).
  • Latini P , FrontiniM, CaputoMet al. CSA and CSB proteins interact with p53 and regulate its Mdm2-dependent ubiquitination. Cell Cycle10(21), 3719–3730 (2011).
  • Leng RP , LinY, MaWet al. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell112(6), 779–791 (2003).
  • Dornan D , WertzI, ShimizuHet al. The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature429(6987), 86–92 (2004).
  • Liu J , ZhangC, WangXLet al. E3 ubiquitin ligase TRIM32 negatively regulates tumor suppressor p53 to promote tumorigenesis. Cell Death Diff.21(11), 1792–1804 (2014).
  • Gonzalez-Cano L , HilljeAL, Fuertes-AlvarezSet al. Regulatory feedback loop between TP73 and TRIM32. Cell Death Dis.4(7), e704 (2013).
  • Lu X , MaO, NguyenTA, JonesSN, OrenM, DonehowerLA. The Wip1 phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop. Cancer Cell12(4), 342–354 (2007).
  • Yan J , JiangJ, ChingAL, WuQ, NgHH, ChinKC. BLIMP1 regulates cell growth through repression of p53 transcription. Proc. Natl Acad. Sci. USA104(6), 1841–1846 (2007).
  • Zhang J , ChoSJ, ShuLet al. Translational repression of p53 by RNPC1, a p53 target overexpressed in lymphomas. Genes Dev.25(14), 1528–1543 (2011).
  • Zhang J , SuB, GongC, XiQ, ChaoT. miR-214 promotes apoptosis and sensitizes breast cancer cells to doxorubicin by targeting the RFWD2-p53 cascade. Biochem. Biophys. Res. Commun.478(1), 337–342 (2016).
  • Zhou X , HaoQ, LiaoPet al. Nerve growth factor receptor negates the tumor suppressor p53 as a feedback regulator. Elife5(Jun), 1–22 (2016).
  • Elwakeel A . Abrogating the interaction between p53 and mortalin (Grp75/HSPA9/mtHsp70) for cancer therapy: the story so far. Front. Cell Dev. Biol.10, 697 (2022).
  • Amick J , SchlangerSE, WachnowskyCet al. Crystal structure of the nucleotide-binding domain of mortalin, the mitochondrial Hsp70 chaperone. Protein Sci.23(6), 833–842 (2014).
  • Radons J . The human HSP70 family of chaperones: where do we stand?Cell Stress Chaperones21(3), 379–404 (2016).
  • Ferré CA , ThouardA, BétournéAet al. HSPA9/mortalin mediates axo-protection and modulates mitochondrial dynamics in neurons. Sci. Rep.11(1), 1–12 (2021).
  • Esfahanian N , KnoblichCD, BowmanGA, RezvaniK. Mortalin: protein partners, biological impacts, pathological roles, and therapeutic opportunities. Front. Cell Dev. Biol.11(February), 1–11 (2023).
  • Texier B , PrimeM, AtamenaD, BelenguerP, SzelechowskiM. Mortalin/Hspa9 involvement and therapeutic perspective in Parkinson's disease. Neural Regen. Res.18(2), 293–298 (2023).
  • Flachbartová Z , KovacechB. Mortalin–a multipotent chaperone regulating cellular processes ranging from viral infection to neurodegeneration. Acta Virol.57(1), 3–15 (2013).
  • D'Silva P , LiuQ, WalterW, CraigEA. Regulated interactions of mtHsp70 with Tim44 at the translocon in the mitochondrial inner membrane. Nat. Struct. Mol. Biol.11(11), 1084–1091 (2004).
  • Kleczewska M , GrabinskaA, JelenMet al. Biochemical convergence of mitochondrial Hsp70 system specialized in iron–sulfur cluster biogenesis. Int. J. Mol. Sci.21(9), 3326 (2020).
  • Pilzer D , FishelsonZ. Mortalin/GRP75 promotes release of membrane vesicles from immune attacked cells and protection from complement-mediated lysis. Int. Immunol.17(9), 1239–1248 (2005).
  • Shih YY , LeeH, NakagawaraAet al. Nuclear GRP75 binds retinoic acid receptors to promote neuronal differentiation of neuroblastoma. PLOS ONE6(10), e26236 (2011).
  • Londono C , OsorioC, GamaV, AlzateO. Mortalin, apoptosis, and neurodegeneration. Biomolecules2(1), 143–164 (2012).
  • Sane S , HafnerA, SrinivasanRet al. UBXN2A enhances CHIP-mediated proteasomal degradation of oncoprotein mortalin-2 in cancer cells. Mol. Oncol.12(10), 1753–1777 (2018).
  • Feng S , HuangQ, DengJet al. DAB2IP suppresses tumor malignancy by inhibiting GRP75-driven p53 ubiquitination in colon cancer. Cancer Lett.532, doi: 10.1016/j.canlet.2022.215588 (2022).
  • Chen X , XuB, LiHet al. Expression of mortalin detected in human liver cancer by tissue microarrays. Anat. Rec. Adv. Integr. Anat. Evol. Biol.294(8), 1344–1351 (2011).
  • Takano S , WadhwaR, YoshiiY, NoseT, KaulSC, MitsuiY. Elevated levels of mortalin expression in human brain tumors. Exp. Cell Res.237(1), 38–45 (1997).
  • Rozenberg P , KocsisJ, SaarM, ProhászkaZ, FüstG, FishelsonZ. Elevated levels of mitochondrial mortalin and cytosolic HSP70 in blood as risk factors in patients with colorectal cancer. Int. J. Cancer133(2), 514–518 (2013).
  • Starenki D , SosonkinaN, HongSK, LloydRV, ParkJI. Mortalin (GRP75/HSPA9) promotes survival and proliferation of thyroid carcinoma cells. Int. J. Mol. Sci.20(9), 2069 (2019).
  • Xu M , JinT, ChenLet al. Mortalin is a distinct bio-marker and prognostic factor in serous ovarian carcinoma. Gene696, 63–71 (2019).
  • Jin H , JiM, ChenLet al. The clinicopathological significance of mortalin overexpression in invasive ductal carcinoma of breast. J. Exp. Clin. Cancer Res.35(1), 1–9 (2016).
  • Sun J , CheSL, PiaoJJ, XuM, ChenLY, LinZH. Mortalin overexpression predicts poor prognosis in early stage of non–small cell lung cancer. Tumor Biol.39(3), 1–9 (2017).
  • Pui-Kei W , Seung-KeunH, SudhakarVet al. A mortalin/HSPA9-mediated switch in tumor-suppressive signaling of Raf/MEK/extracellular signal-regulated kinase. Mol. Cell. Biol.33(20), 4051–4067 (2013).
  • Ma Z , IzumiH, KanaiM, KabuyamaY, AhnNG, FukasawaK. Mortalin controls centrosome duplication via modulating centrosomal localization of p53. Oncogene25(39), 5377–5390 (2006).
  • Yi X , LukJM, LeeNPet al. Association of mortalin (HSPA9) with liver cancer metastasis and prediction for early tumor recurrence. Mol. Cell. Proteomics7(2), 315–325 (2008).
  • Sane S , AbdullahA, BoudreauDAet al. Ubiquitin-like (UBX)-domain-containing protein, UBXN2A, promotes cell death by interfering with the p53-mortalin interactions in colon cancer cells. Cell Death Dis.5(3), e1118 (2014).
  • Wadhwa R , TakanoS, RobertMet al. Inactivation of tumor suppressor p53 by Mot-2, a hsp70 family member. J. Biol. Chem.273(45), 29586–29591 (1998).
  • Kaul SC , TakanoS, ReddelRR, MitsuiY, WadhwaR. Transcriptional Inactivation of p53 by deletions and single amino acid changes in mouse mot-1 protein. Biochem. Biophys. Res. Commun.279(2), 602–606 (2000).
  • Kaul SC , AidaS, YaguchiT, KaurK, WadhwaR. Activation of wild type p53 function by its mortalin-binding, cytoplasmically localizing carboxyl terminus peptides. J. Biol. Chem.280(47), 39373–39379 (2005).
  • Gestl EE , AnneBöttger S. Cytoplasmic sequestration of the tumor suppressor p53 by a heat shock protein 70 family member, mortalin, in human colorectal adenocarcinoma cell lines. Biochem. Biophys. Res. Commun.423(2), 411–416 (2012).
  • Kaul SC , ReddelRR, MitsuiY, WadhwaR. An N-terminal region of Mot-2 binds to p53 in vitro. Neoplasia3(2), 110–114 (2001).
  • Kaul SC , TakanoS, ReddelRR, MitsuiY, WadhwaR. Transcriptional inactivation of p53 by deletions and single amino acid changes in mouse mot-1 protein. Biochem. Biophys. Res. Commun.279(2), 602–606 (2000).
  • Iosefson O , AzemA. Reconstitution of the mitochondrial Hsp70 (mortalin)-p53 interaction using purified proteins–identification of additional interacting regions. FEBS Lett.584(6), 1080–1084 (2010).
  • Moll UM , WolffS, SpeidelD, DeppertW. Transcription-independent pro-apoptotic functions of p53. Curr. Opin. Cell Biol.17(6), 631–636 (2005).
  • Ramraj SK , ElayapillaiSP, PelikanRCet al. Novel ovarian cancer maintenance therapy targeted at mortalin and mutant p53. Int. J. Cancer147(4), 1086–1097 (2020).
  • Yang L , LiuX, HaoJet al. Glucose-regulated protein 75 suppresses apoptosis induced by glucose deprivation in PC12 cells through inhibition of Bax conformational change. Acta Biochim. Biophys. Sin.40(4), 339–348 (2008).
  • Wei B , CaoJ, TianJ-Het al. Mortalin maintains breast cancer stem cells stemness via activation of Wnt/GSK3β/β-catenin signaling pathway. Am. J. Cancer Res.11(6), 2696 (2021).
  • Propper DJ , BraybrookeJP, TaylorDJet al. Phase I trial of the selective mitochondrial toxin MKT 077 in chemo-resistant solid tumours. Ann. Oncol.10(8), 923–927 (1999).
  • Wadhwa R , SugiharaT, YoshidaAet al. Selective toxicity of MKT-077 to cancer cells is mediated by its binding to the hsp70 family protein mot-2 and reactivation of p53 function. Cancer Res.60(24), 6818–6821 (2000).
  • Hong SK , StarenkiD, JohnsonOT, GestwickiJE, ParkJI. Analogs of the heat shock protein 70 inhibitor MKT-077 suppress medullary thyroid carcinoma cells. Int. J. Mol. Sci.23(3), 1063 (2022).
  • Li YX , ZhaiX, LiaoWK, ZhuWF, HeY, GongP. Design, synthesis and biological evaluation of new rhodacyanine analogues as potential antitumor agents. Chin. Chem. Lett.23(4), 415–418 (2012).
  • Putri JF , BhargavaP, DhanjalJKet al. Mortaparib, a novel dual inhibitor of mortalin and PARP1, is a potential drug candidate for ovarian and cervical cancers. J. Exp. Clin. Cancer Res.38(1), 1–15 (2019).
  • Sari AN , ElwakeelA, DhanjalJKet al. Identification and characterization of MortaparibPlus–a novel triazole derivative that targets mortalin-p53 interaction and inhibits cancer-cell proliferation by wild-type p53-dependent and -independent mechanisms. Cancers (Basel)13(4), 835 (2021).
  • Meidinna HN , ShefrinS, SariANet al. Identification of a new member of mortaparib class of inhibitors that target mortalin and PARP1. Front. Cell Dev. Biol.10, doi: 10.3389/fcell.2022.918970 (2022).
  • Benbrook DM , NammalwarB, LongAet al. SHetA2 interference with mortalin binding to p66shc and p53 identified using drug-conjugated magnetic microspheres. Invest. New Drugs32(3), 412–423 (2014).
  • Benbrook DM . SHetA2 attack on mortalin and colleagues in cancer therapy and prevention. Front. Cell Dev. Biol.10(February), 1–13 (2022).
  • Chandra V , RaiR, BenbrookDM. Utility and mechanism of sheta2 and paclitaxel for treatment of endometrial cancer. Cancers (Basel)13(10), 1–19 (2021).
  • Park SH , BaekKH, ShinI, ShinI. Subcellular Hsp70 inhibitors promote cancer cell death via different mechanisms. Cell Chem. Biol.25(10), 1242–1254 (2018).
  • Grover A , PriyandokoD, GaoRet al. Withanone binds to mortalin and abrogates mortalin–p53 complex: computational and experimental evidence. Int. J. Biochem. Cell Biol.44(3), 496–504 (2012).
  • Wadhwa R , NigamN, BhargavaPet al. Molecular characterization and enhancement of anticancer activity of caffeic acid phenethyl ester by γ cyclodextrin. J. Cancer7(13), 1755–1771 (2016).
  • Bhargava P , GroverA, NigamNet al. Anticancer activity of the supercritical extract of Brazilian green propolis and its active component, artepillin C: bioinformatics and experimental analyses of its mechanisms of action. Int. J. Oncol.52(3), 925–932 (2018).
  • Garg S , AfzalS, ElwakeelAet al. Marine carotenoid fucoxanthin possesses anti-metastasis activity: molecular evidence. Mar. Drugs17(6), 338 (2019).
  • Nigam N , GroverA, GoyalSet al. Targeting mortalin by embelin causes activation of tumor suppressor p53 and deactivation of metastatic signaling in human breast cancer cells. PLOS ONE10(9), e0138192 (2015).
  • Kurnia Hartati F , BesariDjauhari A. Potential of black rice (Oryza sativa L.) as anticancer through mortalin-p53 complex inhibitors. Biointerface Res. Appl. Chem.10(5), 6174–6181 (2020).
  • Nagpal N , GoyalS, DhanjalJKet al. Molecular dynamics-based identification of novel natural mortalin–p53 abrogators as anticancer agents. J. Recept. Signal Transduct.37(1), 8–16 (2016).
  • Abdullah A , SaneS, BranickKAet al. A plant alkaloid, veratridine, potentiates cancer chemosensitivity by UBXN2A-dependent inhibition of an oncoprotein, mortalin-2. Oncotarget6(27), 23561–23581 (2015).
  • Utomo DH , WidodoN, Rifa'iM. Identifications small molecules inhibitor of p53-mortalin complex for cancer drug using virtual screening. Bioinformation8(9), 429 (2012).
  • Sari AN , BhargavaP, DhanjalJKet al. Combination of withaferin-A and CAPE provides superior anticancer potency: bioinformatics and experimental evidence to their molecular targets and mechanism of action. Cancers (Basel)12(5), 1160 (2020).
  • Pham MQ , TranTHV, PhamQL, GairinJE. In silico analysis of the binding properties of solasonine to mortalin and p53, and in vitro pharmacological studies of its apoptotic and cytotoxic effects on human HepG2 and Hep3b hepatocellular carcinoma cells. Fundam. Clin. Pharmacol.33(4), 385–396 (2019).
  • Buchwald P . Small-molecule protein-protein interaction inhibitors: therapeutic potential in light of molecular size, chemical space, and ligand binding efficiency considerations. IUBMB Life62(10), 724–731 (2010).
  • Cui W , AouidateA, WangS, YuQ, LiY, YuanS. Discovering anti-cancer drugs via computational methods. Front. Pharmacol.11, 733 (2020).
  • Macalino SJY , BasithS, ClavioNAB, ChangH, KangS, ChoiS. Evolution of in silico strategies for protein-protein interaction drug discovery. Molecules23(8), 1963 (2018).
  • Wang L , WangN, ZhangWet al. Therapeutic peptides: current applications and future directions. Signal Transduct. Target. Ther.7(1), 1–27 (2022).
  • Kaul SC , AidaS, YaguchiT, KaurK, WadhwaR. Activation of wild type p53 function by its mortalin-binding, cytoplasmically localizing carboxyl terminus peptides. J. Biol. Chem.280(47), 39373–39379 (2005).
  • Bulcha JT , WangY, MaH, TaiPWL, GaoG. Viral vector platforms within the gene therapy landscape. Signal Transduct. Target. Ther.6(1), 1–24 (2021).
  • Yoo JY , RyuJ, GaoRet al. Tumor suppression by apoptotic and anti-angiogenic effects of mortalin-targeting adeno-oncolytic virus. J. Gene Med.12(7), 586–595 (2010).
  • Yu AM , ChoiYH, TuMJ. RNA drugs and RNA targets for small molecules: principles, progress, and challenges. Pharmacol. Rev.72(4), 862–898 (2020).
  • Sari S , TomekP, LeungE, ReynissonJ. Discovery and characterisation of dual inhibitors of tryptophan 2,3-dioxygenase (TDO2) and indoleamine 2,3-dioxygenase 1 (IDO1) using virtual screening. Molecules24(23), 1–19 (2019).
  • Zhao L , ZhaoJ, ZhongK, TongA, JiaD. Targeted protein degradation: mechanisms, strategies and application. Signal Transduct. Target. Ther.7(1), 1–13 (2022).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.