5,563
Views
52
CrossRef citations to date
0
Altmetric
Review

Hsp90 inhibitors as senolytic drugs to extend healthy aging

ORCID Icon, &
Pages 1048-1055 | Received 01 Feb 2018, Accepted 07 May 2018, Published online: 23 Jul 2018

References

  • Lopez-Otin C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194–1217. PubMed PMID: 23746838; PubMed Central PMCID: PMC3836174.
  • Wang E. Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Res. 1995 Jun 1;55(11):2284–2292. PubMed PMID: 7757977.
  • Campisi J. Cancer and ageing: rival demons? Nat Rev Cancer. 2003 May;3(5):339–349. PubMed PMID: 12724732.
  • Coppe JP, Patil CK, Rodier F, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008 Dec 02;6(12):2853–2868. PubMed PMID: 19053174; PubMed Central PMCID: PMCPMC2592359.
  • Baker DJ, Childs BG, Durik M, et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016 Feb 11;530(7589):184–189. PubMed PMID: 26840489; PubMed Central PMCID: PMCPMC4845101.
  • Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011 Nov 02;479(7372):232–236. PubMed PMID: 22048312; PubMed Central PMCID: PMC3468323.
  • Xu M, Bradley EW, Weivoda MM, et al. Transplanted senescent cells induce an osteoarthritis-like condition in mice. J Gerontol A Biol Sci Med Sci. 2017 Jun 01;72(6):780–785. PubMed PMID: 27516624.
  • Kirkland JL, Tchkonia T, Zhu Y, et al. The clinical potential of senolytic drugs. J Am Geriatr Soc. 2017 Sep 04 PubMed PMID: 28869295. DOI:10.1111/jgs.14969.
  • Kirkland JL, Tchkonia T. Cellular senescence: a translational perspective. EBioMedicine. 2017 Apr 12. PubMed PMID: 28416161. DOI:10.1016/j.ebiom.2017.04.013
  • Fuhrmann-Stroissnigg H, Ling YY, Zhao J, et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun. 2017 Sep 04;8(1):422. PubMed PMID: 28871086; PubMed Central PMCID: PMC5583353.
  • Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015 Aug;14(4):644–658. PubMed PMID: 25754370; PubMed Central PMCID: PMC4531078.
  • Farr JN, Xu M, Weivoda MM, et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat Med. 2017 Sep;23(9):1072–1079. PubMed PMID: 28825716.
  • Chang J, Wang Y, Shao L, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med. 2016 Jan;22(1):78–83. PubMed PMID: 26657143; PubMed Central PMCID: PMCPMC4762215.
  • Zhu Y, Doornebal EJ, Pirtskhalava T, et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY). 2017 Mar 08;9(3):955–963. PubMed PMID: 28273655; PubMed Central PMCID: PMC5391241.
  • Moncsek A, Al-Suraih MS, Trussoni CE, et al. Targeting senescent cholangiocytes and activated fibroblasts with Bcl-xL inhibitors ameliorates fibrosis in Mdr2-/- mice. Hepatology. 2017 Aug 12 PubMed PMID: 28802066. DOI:10.1002/hep.29464.
  • Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell. 2016 Jun;15(3):428–435. PubMed PMID: 26711051; PubMed Central PMCID: PMCPMC4854923.
  • Yosef R, Pilpel N, Tokarsky-Amiel R, et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun. 2016 Apr 06;7:11190. PubMed PMID: 27048913; PubMed Central PMCID: PMCPMC4823827.
  • Baar MP, Brandt RM, Putavet DA, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell. 2017 Mar 23;169(1):132–147 e16. PubMed PMID: 28340339.
  • Wang Y, Chang J, Liu X, et al. Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging (Albany NY). 2016 Nov 19;8(11):2915–2926. PubMed PMID: 27913811; PubMed Central PMCID: PMC5191878.
  • van Deursen JM. The role of senescent cells in ageing. Nature. 2014 May 22;509(7501):439–446. PubMed PMID: 24848057; PubMed Central PMCID: PMC4214092.
  • Ritossa FM. A new puffing pattern induced by temperature shock and DNP in drosophila. Experientia. 1962;18(12): 571. PubMed PMID: 14163779.
  • Courgeon AM, Maisonhaute C, Best-Belpomme M. Heat shock proteins are induced by cadmium in Drosophila cells. Exp Cell Res. 1984 Aug;153(2):515–521. PubMed PMID: 6734754.
  • Trott A, West JD, Klaic L, et al. Activation of heat shock and antioxidant responses by the natural product celastrol: transcriptional signatures of a thiol-targeted molecule. Mol Biol Cell. 2008 Mar;19(3):1104–1112. PubMed PMID: 18199679; PubMed Central PMCID: PMC2262981.
  • Kregel KC. Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance. J Appl Physiol (1985). 2002 May;92(5):2177–2186. PubMed PMID: 11960972.
  • Morimoto RI. Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev. 1998 Dec 15;12(24):3788–3796. PubMed PMID: 9869631.
  • Dai C, Whitesell L, Rogers AB, et al. Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell. 2007 Sep 21;130(6):1005–1018. PubMed PMID: 17889646; PubMed Central PMCID: PMC2586609.
  • Jee H. Size dependent classification of heat shock proteins: a mini-review. J Exerc Rehabil. 2016 Aug;12(4):255–259. PubMed PMID: 27656620; PubMed Central PMCID: PMC5031383.
  • Richter K, Haslbeck M, Buchner J. The heat shock response: life on the verge of death. Mol Cell. 2010 Oct 22;40(2):253–266. PubMed PMID: 20965420.
  • Arrigo AP, Simon S, Gibert B, et al. Hsp27 (HspB1) and alphaB-crystallin (HspB5) as therapeutic targets. FEBS Lett. 2007 Jul 31;581(19):3665–3674. PubMed PMID: 17467701.
  • Hartl FU. Molecular chaperones in cellular protein folding. Nature. 1996 Jun 13;381(6583):571–579. PubMed PMID: 8637592.
  • Taipale M, Jarosz DF, Lindquist S. HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat Rev Mol Cell Biol. 2010 Jul;11(7):515–528. PubMed PMID: 20531426.
  • Lindquist S, Craig EA. The heat-shock proteins. Annu Rev Genet. 1988;22:631–677. PubMed PMID: 2853609.
  • Trepel J, Mollapour M, Giaccone G, et al. Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer. 2010 Aug;10(8):537–549. PubMed PMID: 20651736.
  • Barrott JJ, Haystead TA. Hsp90, an unlikely ally in the war on cancer. FEBS J. 2013 Mar;280(6):1381–1396. PubMed PMID: 23356585; PubMed Central PMCID: PMC3815692.
  • Sreedhar AS, Kalmar E, Csermely P, et al. Hsp90 isoforms: functions, expression and clinical importance. FEBS Lett. 2004 Mar 26;562(1–3):11–15. PubMed PMID: 15069952.
  • Seo YH. Organelle-specific Hsp90 inhibitors. Arch Pharm Res. 2015 Sep;38(9):1582–1590. 10.1007/s12272-015-0636-1. PubMed PMID: 26195286.
  • Plescia J, Salz W, Xia F, et al. Rational design of shepherdin, a novel anticancer agent. Cancer Cell. 2005 May;7(5):457–468. PubMed PMID: 15894266.
  • Kang BH, Plescia J, Dohi T, et al. Regulation of tumor cell mitochondrial homeostasis by an organelle-specific Hsp90 chaperone network. Cell. 2007 Oct 19;131(2):257–270. PubMed PMID: 17956728.
  • Patel PD, Yan P, Seidler PM, et al. Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2. Nat Chem Biol. 2013 Nov;9(11):677–684. PubMed PMID: 23995768; PubMed Central PMCID: PMC3982621.
  • Blair LJ, Sabbagh JJ, Dickey CA. Targeting Hsp90 and its co-chaperones to treat Alzheimer’s disease. Expert Opin Ther Targets. 2014 Oct;18(10):1219–1232. PubMed PMID: 25069659; PubMed Central PMCID: PMC4625388.
  • Falsone SF, Kungl AJ, Rek A, et al. The molecular chaperone Hsp90 modulates intermediate steps of amyloid assembly of the Parkinson-related protein alpha-synuclein. J Biol Chem. 2009 Nov 06;284(45):31190–31199. PubMed PMID: 19759002; PubMed Central PMCID: PMC2781518.
  • Whitesell L, Lindquist SL. HSP90 and the chaperoning of cancer. Nat Rev Cancer. 2005 Oct;5(10):761–772. PubMed PMID: 16175177.
  • Prodromou C. Mechanisms of Hsp90 regulation. Biochem J. 2016 Aug 15;473(16):2439–2452. PubMed PMID: 27515256; PubMed Central PMCID: PMC4980810.
  • Dasuri K, Zhang L, Ebenezer P, et al. Aging and dietary restriction alter proteasome biogenesis and composition in the brain and liver. Mech Ageing Dev. 2009 Nov-Dec;130(11–12):777–783. PubMed PMID: 19896962; PubMed Central PMCID: PMC2942759.
  • Echeverria PC, Bernthaler A, Dupuis P, et al. An interaction network predicted from public data as a discovery tool: application to the Hsp90 molecular chaperone machine. PLoS One. 2011;6(10):e26044. PubMed PMID: 22022502; PubMed Central PMCID: PMC3195953.
  • Schopf FH, Biebl MM, Buchner J. The HSP90 chaperone machinery. Nat Rev Mol Cell Biol. 2017 Jun;18(6):345–360. PubMed PMID: 28429788.
  • Zuehlke A, Johnson JL. Hsp90 and co-chaperones twist the functions of diverse client proteins. Biopolymers. 2010 Mar;93(3):211–217. PubMed PMID: 19697319; PubMed Central PMCID: PMC2810645.
  • Li J, Soroka J, Buchner J. The Hsp90 chaperone machinery: conformational dynamics and regulation by co-chaperones. Biochim Biophys Acta. 2012 Mar;1823(3):624–635. PubMed PMID: 21951723..
  • Sato S, Fujita N, Tsuruo T. Modulation of Akt kinase activity by binding to Hsp90. Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10832–10837. PubMed PMID: 10995457; PubMed Central PMCID: PMC27109.
  • Han SY, Ko A, Kitano H, et al. Molecular chaperone HSP90 is necessary to prevent cellular senescence via lysosomal degradation of p14ARF. Cancer Res. 2017 Jan 15;77(2):343–354. PubMed PMID: 27793846.
  • di Martino S, Amoreo CA, Nuvoli B, et al. HSP90 inhibition alters the chemotherapy-driven rearrangement of the oncogenic secretome. Oncogene. 2018 Mar;37(10):1369–1385. 10.1038/s41388-017-0044-8. PubMed PMID: 29311642.
  • Pennisi R, Ascenzi P, di Masi A. Hsp90: a new player in DNA repair? Biomolecules. 2015 Oct 16;5(4):2589–2618. PubMed PMID: 26501335; PubMed Central PMCID: PMC4693249.
  • Stecklein SR, Kumaraswamy E, Behbod F, et al. BRCA1 and HSP90 cooperate in homologous and non-homologous DNA double-strand-break repair and G2/M checkpoint activation. Proc Natl Acad Sci U S A. 2012 Aug 21;109(34):13650–13655. PubMed PMID: 22869732; PubMed Central PMCID: PMC3427093.
  • Spiegelberg D, Dascalu A, Mortensen AC, et al. The novel HSP90 inhibitor AT13387 potentiates radiation effects in squamous cell carcinoma and adenocarcinoma cells. Oncotarget. 2015 Nov 03;6(34):35652–35666. PubMed PMID: 26452257; PubMed Central PMCID: PMC4742132.
  • Freitas AA, De Magalhaes JP. A review and appraisal of the DNA damage theory of ageing. Mutat Res. 2011 Jul-Oct;728(1–2):12–22. PubMed PMID: 21600302.
  • Noguchi M, Yu D, Hirayama R, et al. Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin. Biochem Biophys Res Commun. 2006 Dec 22;351(3):658–663. PubMed PMID: 17083915.
  • Quanz M, Herbette A, Sayarath M, et al. Heat shock protein 90alpha (Hsp90alpha) is phosphorylated in response to DNA damage and accumulates in repair foci. J Biol Chem. 2012 Mar 16;287(12):8803–8815. PubMed PMID: 22270370; PubMed Central PMCID: PMC3308794.
  • Tilstra JS, Robinson AR, Wang J, et al. NF-kappaB inhibition delays DNA damage-induced senescence and aging in mice. J Clin Invest. 2012 Jul;122(7):2601–2612. PubMed PMID: 22706308; PubMed Central PMCID: PMC3386805.
  • Tsutsumi S, Scroggins B, Koga F, et al. A small molecule cell-impermeant Hsp90 antagonist inhibits tumor cell motility and invasion. Oncogene. 2008 Apr 10;27(17):2478–2487. PubMed PMID: 17968312; PubMed Central PMCID: PMC2754825.
  • Li W, Sahu D, Tsen F. Secreted heat shock protein-90 (Hsp90) in wound healing and cancer. Biochim Biophys Acta. 2012 Mar;1823(3):730–741. PubMed PMID: 21982864; PubMed Central PMCID: PMC3266443.
  • Becker B, Multhoff G, Farkas B, et al. Induction of Hsp90 protein expression in malignant melanomas and melanoma metastases. Exp Dermatol. 2004 Jan;13(1):27–32. PubMed PMID: 15009113.
  • Eustace BK, Jay DG. Extracellular roles for the molecular chaperone, hsp90. Cell Cycle. 2004 Sep;3(9):1098–1100. PubMed PMID: 15326368.
  • Tchkonia T, Zhu Y, van Deursen J, et al. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest. 2013 Mar;123(3):966–972. PubMed PMID: 23454759; PubMed Central PMCID: PMC3582125.
  • Kuilman T, Peeper DS. Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer. 2009 Feb;9(2):81–94. PubMed PMID: 19132009.
  • Thuringer D, Hammann A, Benikhlef N, et al. Transactivation of the epidermal growth factor receptor by heat shock protein 90 via Toll-like receptor 4 contributes to the migration of glioblastoma cells. J Biol Chem. 2011 Feb 4;286(5):3418–3428. PubMed PMID: 21127066; PubMed Central PMCID: PMC3030348.
  • Sidera K, Patsavoudi E. Extracellular HSP90: conquering the cell surface. Cell Cycle. 2008 Jun 1;7(11):1564–1568. doi:10.4161/cc.7.11.6054. PubMed PMID: 18469526.
  • McCready J, Wong DS, Burlison JA, et al. An Impermeant Ganetespib Analog Inhibits Extracellular Hsp90-Mediated Cancer Cell Migration that Involves Lysyl Oxidase 2-like Protein. Cancers (Basel). 2014 Apr 30;6(2):1031–1046. doi:10.3390/cancers6021031. PubMed PMID: 24785146; PubMed Central PMCID: PMC4074815.
  • Stellas D, El Hamidieh A, Patsavoudi E. Monoclonal antibody 4C5 prevents activation of MMP2 and MMP9 by disrupting their interaction with extracellular HSP90 and inhibits formation of metastatic breast cancer cell deposits. BMC Cell Biol. 2010 Jul 5;11:51. doi:10.1186/1471-2121-11-51. PubMed PMID: 20602761; PubMed Central PMCID: PMC2914660.
  • Song HY, Dunbar JD, Zhang YX, et al. Identification of a protein with homology to hsp90 that binds the type 1 tumor necrosis factor receptor. J Biol Chem. 1995 Feb 24;270(8):3574–3581. PubMed PMID: 7876093.
  • Felts SJ, Owen BA, Nguyen P, et al. The hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties. J Biol Chem. 2000 Feb 4;275(5):3305–3312. PubMed PMID: 10652318.
  • Chen B, Piel WH, Gui L, et al. The HSP90 family of genes in the human genome: insights into their divergence and evolution. Genomics. 2005 Dec;86(6):627–637. PubMed PMID: 16269234.
  • Leskovar A, Wegele H, Werbeck ND, et al. The ATPase cycle of the mitochondrial Hsp90 analog Trap1. J Biol Chem. 2008 Apr 25;283(17):11677–11688. PubMed PMID: 18287101.
  • Altieri DC, Stein GS, Lian JB, et al. TRAP-1, the mitochondrial Hsp90. Biochim Biophys Acta. 2012 Mar;1823(3):767–773. PubMed PMID: 21878357; PubMed Central PMCID: PMC3263322.
  • Masuda Y, Shima G, Aiuchi T, et al. Involvement of tumor necrosis factor receptor-associated protein 1 (TRAP1) in apoptosis induced by beta-hydroxyisovalerylshikonin. J Biol Chem. 2004 Oct 8;279(41):42503–42515. PubMed PMID: 15292218.
  • Pridgeon JW, Olzmann JA, Chin LS, et al. PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol. 2007 Jul;5(7):e172. PubMed PMID: 17579517; PubMed Central PMCID: PMC1892574.
  • Masgras I, Sanchez-Martin C, Colombo G, et al. The chaperone TRAP1 as a modulator of the mitochondrial adaptations in cancer cells. Front Oncol. 2017;7:58. PubMed PMID: 28405578; PubMed Central PMCID: PMC5370238.
  • Leav I, Plescia J, Goel HL, et al. Cytoprotective mitochondrial chaperone TRAP-1 as a novel molecular target in localized and metastatic prostate cancer. Am J Pathol. 2010 Jan;176(1):393–401. PubMed PMID: 19948822; PubMed Central PMCID: PMC2797899.
  • Gao JY, Song BR, Peng JJ, et al. Correlation between mitochondrial TRAP-1 expression and lymph node metastasis in colorectal cancer. World J Gastroenterol. 2012 Nov 7;18(41):5965–5971. PubMed PMID: 23139614; PubMed Central PMCID: PMC3491605.
  • Zhang B, Wang J, Huang Z, et al. Aberrantly upregulated TRAP1 is required for tumorigenesis of breast cancer. Oncotarget. 2015 Dec 29;6(42):44495–44508. PubMed PMID: 26517089; PubMed Central PMCID: PMC4792571.
  • Amoroso MR, Matassa DS, Agliarulo I, et al. TRAP1 downregulation in human ovarian cancer enhances invasion and epithelial-mesenchymal transition. Cell Death Dis. 2016 Dec 15;7(12):e2522. PubMed PMID: 27977010; PubMed Central PMCID: PMC5260997.
  • Baines CP, Kaiser RA, Purcell NH, et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature. 2005 Mar 31;434(7033):658–662. PubMed PMID: 15800627.
  • Basso E, Fante L, Fowlkes J, et al. Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. J Biol Chem. 2005 May 13;280(19):18558–18561. PubMed PMID: 15792954.
  • Nakagawa T, Shimizu S, Watanabe T, et al. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature. 2005 Mar 31;434(7033):652–658. PubMed PMID: 15800626.
  • Kang BH, Altieri DC. Compartmentalized cancer drug discovery targeting mitochondrial Hsp90 chaperones. Oncogene. 2009 Oct 22;28(42):3681–3688. PubMed PMID: 19648961; PubMed Central PMCID: PMC2766018.
  • Kang BH, Plescia J, Song HY, et al. Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial Hsp90. J Clin Invest. 2009 Mar;119(3):454–464. PubMed PMID: 19229106; PubMed Central PMCID: PMC2648691.
  • Landriscina M, Laudiero G, Maddalena F, et al. Mitochondrial chaperone Trap1 and the calcium binding protein Sorcin interact and protect cells against apoptosis induced by antiblastic agents. Cancer Res. 2010 Aug 15;70(16):6577–6586. PubMed PMID: 20647321.
  • Condelli V, Piscazzi A, Sisinni L, et al. TRAP1 is involved in BRAF regulation and downstream attenuation of ERK phosphorylation and cell-cycle progression: a novel target for BRAF-mutated colorectal tumors. Cancer Res. 2014 Nov 15;74(22):6693–6704. PubMed PMID: 25239454.
  • Lisanti S, Tavecchio M, Chae YC, et al. Deletion of the mitochondrial chaperone TRAP-1 uncovers global reprogramming of metabolic networks. Cell Rep. 2014 Aug 7;8(3):671–677. PubMed PMID: 25088416; PubMed Central PMCID: PMC4127146.
  • Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011 Nov 25;334(6059):1081–1086. PubMed PMID: 22116877.
  • Rutkowski DT, Hegde RS. Regulation of basal cellular physiology by the homeostatic unfolded protein response. J Cell Biol. 2010 May 31;189(5):783–794. PubMed PMID: 20513765; PubMed Central PMCID: PMC2878945.
  • Schroder M, Kaufman RJ. ER stress and the unfolded protein response. Mutat Res. 2005 Jan 6;569(1–2):29–63. PubMed PMID: 15603751.
  • Eletto D, Dersh D, Argon Y. GRP94 in ER quality control and stress responses. Semin Cell Dev Biol. 2010 Jul;21(5):479–485. PubMed PMID: 20223290; PubMed Central PMCID: PMC3676867.
  • Marzec M, Eletto D, Argon Y. GRP94: an HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum. Biochim Biophys Acta. 2012 Mar;1823(3):774–787. PubMed PMID: 22079671; PubMed Central PMCID: PMC3443595.
  • Brown MK, Naidoo N. The endoplasmic reticulum stress response in aging and age-related diseases. Front Physiol. 2012;3:263. PubMed PMID: 22934019; PubMed Central PMCID: PMC3429039.
  • Naidoo N, Ferber M, Master M, et al. Aging impairs the unfolded protein response to sleep deprivation and leads to proapoptotic signaling. J Neurosci. 2008 Jun 25;28(26):6539–6548. PubMed PMID: 18579727; PubMed Central PMCID: PMC2925257.
  • Paz Gavilan M, Vela J, Castano A, et al. Cellular environment facilitates protein accumulation in aged rat hippocampus. Neurobiol Aging. 2006 Jul;27(7):973–982. PubMed PMID: 15964666.
  • Nuss JE, Choksi KB, DeFord JH, et al. Decreased enzyme activities of chaperones PDI and BiP in aged mouse livers. Biochem Biophys Res Commun. 2008 Jan 11;365(2):355–361. PubMed PMID: 17996725; PubMed Central PMCID: PMC2238339.
  • Minakshi R, Rahman S, Jan AT, et al. Implications of aging and the endoplasmic reticulum unfolded protein response on the molecular modality of breast cancer. Exp Mol Med. 2017 Nov 10;49(11):e389. PubMed PMID: 29123254.
  • Ogata M, Hino S, Saito A, et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol. 2006 Dec;26(24):9220–9231. PubMed PMID: 17030611; PubMed Central PMCID: PMC1698520.
  • Selkoe DJ. Folding proteins in fatal ways. Nature. 2003 Dec 18;426(6968):900–904. PubMed PMID: 14685251.
  • Zhu G, Lee AS. Role of the unfolded protein response, GRP78 and GRP94 in organ homeostasis. J Cell Physiol. 2015 Jul;230(7):1413–1420. PubMed PMID: 25546813; PubMed Central PMCID: PMC4725317.
  • Ryu EJ, Harding HP, Angelastro JM, et al. Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson’s disease. J Neurosci. 2002 Dec 15;22(24):10690–10698. PubMed PMID: 12486162.
  • Forman MS, Lee VM, Trojanowski JQ. ‘Unfolding’ pathways in neurodegenerative disease. Trends Neurosci. 2003 Aug;26(8):407–410. PubMed PMID: 12900170..
  • Reddy PH, Williams M, Tagle DA. Recent advances in understanding the pathogenesis of Huntington’s disease. Trends Neurosci. 1999 Jun;22(6):248–255. PubMed PMID: 10354600.
  • Jaronen M, Goldsteins G, Koistinaho J. ER stress and unfolded protein response in amyotrophic lateral sclerosis-a controversial role of protein disulphide isomerase. Front Cell Neurosci. 2014;8:402. PubMed PMID: 25520620; PubMed Central PMCID: PMC4251436.
  • Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006 Dec 14;444(7121):860–867. PubMed PMID: 17167474.
  • Zhang K, Kaufman RJ. From endoplasmic-reticulum stress to the inflammatory response. Nature. 2008 Jul 24;454(7203):455–462. PubMed PMID: 18650916; PubMed Central PMCID: PMC2727659.
  • Staron M, Yang Y, Liu B, et al. gp96, an endoplasmic reticulum master chaperone for integrins and Toll-like receptors, selectively regulates early T and B lymphopoiesis. Blood. 2010 Mar 25;115(12):2380–2390. doi:10.1182/blood-2009-07-233031. PubMed PMID: 19965672; PubMed Central PMCID: PMC2845896.
  • Schaiff WT, Hruska KA, Jr., McCourt DW, et al. HLA-DR associates with specific stress proteins and is retained in the endoplasmic reticulum in invariant chain negative cells. J Exp Med. 1992 Sep 1;176(3):657–666. PubMed PMID: 1512535; PubMed Central PMCID: PMC2119345.
  • Mao C, Wang M, Luo B, et al. Targeted mutation of the mouse Grp94 gene disrupts development and perturbs endoplasmic reticulum stress signaling. PLoS One. 2010 May 26;5(5):e10852. PubMed PMID: 20520781; PubMed Central PMCID: PMC2877114.
  • Chhabra S, Jain S, Wallace C, et al. High expression of endoplasmic reticulum chaperone grp94 is a novel molecular hallmark of malignant plasma cells in multiple myeloma. J Hematol Oncol. 2015 Jun 25;8:77. PubMed PMID: 26108343; PubMed Central PMCID: PMC4483199.
  • Huang CY, Batzorig U, Cheng WL, et al. Glucose-regulated protein 94 mediates cancer progression via AKT and eNOS in hepatocellular carcinoma. Tumour Biol. 2016 Apr;37(4):4295–4304. PubMed PMID: 26493996.
  • Crowley VM, Huard DJE, Lieberman RL, et al. Second generation Grp94-Selective inhibitors provide opportunities for the inhibition of metastatic cancer. Chemistry. 2017 Nov 7;23(62):15775–15782. PubMed PMID: 28857290.
  • Laberge RM, Sun Y, Orjalo AV, et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol. 2015 Aug;17(8):1049–1061. PubMed PMID: 26147250; PubMed Central PMCID: PMCPMC4691706.
  • Herranz N, Gallage S, Mellone M, et al. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat Cell Biol. 2015 Sep;17(9):1205–1217. PubMed PMID: 26280535; PubMed Central PMCID: PMCPMC4589897.
  • Ovadya Y, Krizhanovsky V. Strategies targeting cellular senescence. J Clin Invest. 2018 Apr 2;128(4):1247–1254. PubMed PMID: 29608140; PubMed Central PMCID: PMC5873866.
  • Schafer MJ, White TA, Iijima K, et al. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun. 2017 Feb 23;8:14532. PubMed PMID: 28230051; PubMed Central PMCID: PMC5331226.
  • Jeon OH, Kim C, Laberge RM, et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 2017 Apr 24 PubMed PMID: 28436958. DOI:10.1038/nm.4324.
  • Samaraweera L, Adomako A, Rodriguez-Gabin A, et al. A novel indication for panobinostat as a senolytic drug in NSCLC and HNSCC. Sci Rep. 2017 May 15;7(1):1900. PubMed PMID: 28507307; PubMed Central PMCID: PMC5432488.

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.