Inhibiting the HSP90 chaperone destabilizes macrophage migration inhibitory factor and thereby inhibits breast tumor progression

Schulz, Ramona; Marchenko, Natalia D.; Holembowski, Lena; Fingerle‐Rowson, Günter; Pešić, Marina; Zender, Lars; Dobbelstein, Matthias; Mol, Ute M.

doi:10.1084/jem.201111172093c

Cited by 21 publications

(30 citation statements)

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“…1 Among these clients are tumor drivers such as mutant p53 (ref. 2) and MIF, 3 but also cell cycle regulators like Wee1(ref. 4) and Chk1, 5 as well as DNA repair proteins such as those governing the Fanconi Anemia DNA repair pathway.…”

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confidence: 99%

Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

et al. 2016

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All current regimens for treating ovarian cancer center around carboplatin as standard first line. The HSP90 inhibitor ganetespib is currently being assessed in advanced clinical oncology trials. Thus, we tested the combined effects of ganetespib and carboplatin on a panel of 15 human ovarian cancer lines. Strikingly, the two drugs strongly synergized in cytotoxicity in tumor cells lacking wild-type p53. Mechanistically, ganetespib and carboplatin in combination, but not individually, induced persistent DNA damage causing massive global chromosome fragmentation. Live-cell microscopy revealed chromosome fragmentation occurring to a dramatic degree when cells condensed their chromatin in preparation for mitosis, followed by cell death in mitosis or upon aberrant exit from mitosis. HSP90 inhibition caused the rapid decay of key components of the Fanconi anemia pathway required for repair of carboplatin-induced interstrand crosslinks (ICLs), as well as of cell cycle checkpoint mediators. Overexpressing FancA rescued the DNA damage induced by the drug combination, indicating that FancA is indeed a key client of Hsp90 that enables cancer cell survival in the presence of ICLs. Conversely, depletion of nuclease DNA2 prevented chromosomal fragmentation, pointing to an imbalance of defective repair in the face of uncontrolled nuclease activity as mechanistic basis for the observed premitotic DNA fragmentation. Importantly, the drug combination induced robust antitumor activity in xenograft models, again accompanied with depletion of FancA. In sum, our findings indicate that ganetespib strongly potentiates the antitumor efficacy of carboplatin by causing combined inhibition of DNA repair and cell cycle control mechanisms, thus triggering global chromosome disruption, aberrant mitosis and cell death. 6 This provides a strong rationale for HSP90 inhibitors in cancer therapy 7 and raises the possibility that HSP90 inhibitors can be used in combination with DNAdamaging chemotherapeutics. 8 Ovarian cancer is among the most common gynecological tumor types and carries the worst prognosis. HSP90 is highly expressed in advanced ovarian carcinoma 9 and thus constitutes a potential therapeutic drug target. 10 In support, HSP90 inhibitors were found effective against ovarian cancer in preclinical models, 11-14 alone or in combination with conventional chemotherapy. 15,16 Carboplatin is the key component of all current first-line therapies for ovarian carcinoma. However, while initially often responding with regression, most tumors relapse and develop resistance within less than a year. 17,18 Like other platinum compounds, carboplatin acts by forming crosslinks within DNA. 17 Platinum compounds form intrastrand DNA lesions but also interstrand crosslinks (ICLs) by covalently linking opposite DNA strands. Such ICLs represent major obstacles to the DNA replication fork 19 and are therefore considered the principal toxic lesion of carboplatin's mode of action. The ICLs can only be removed by a sophisticated DNA repair systemthe Fanconi ...

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Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

et al. 2016

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“…In addition, HSP90 is upregulated in ADPKD kidneys, and HSP90 inhibition slows cyst growth in a mouse model of ADPKD (44). It has been reported that inhibiting HSP90 destabilizes MIF in breast cancer cells (45), suggesting that the elevated MIF levels in ADPKD may be mediated through HSP90 stabilization (Figure 8). In support of this idea, we found that HSP90 inhibition decreased MIF levels in Pkd1 mutant renal epithelial cells (Supplemental Figure 15).…”

Section: Mif Is a Soluble Factor Secreted By Adpkd Cells Into Adpkdcomentioning

confidence: 92%

Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease

et al. 2015

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“…It is assumed that hydrolysis of ATP to ADP, at the nucleotide-binding site energizes the functions of the HSP90 chaperone complex (Bagatell and Whitesell 2004). Several inhibitors of HSP90 have been recognized; the most well categorized ones are derivatives of the benzoquinone ansamycin antibiotic geldanamycin (GA) and the macrolide antibiotic radicicol that either bind to the N-terminal domain, nucleotide binding site, inhibit the ATPase activity, ADP-ATP exchange activity, increase the usage of ubiquitin ligases to the HSP90 chaperone complex and consequently leading to increased degradation of client proteins by the proteasome pathway (Fukuyo et al, 2010).Geldanamycin derivative17-allylamino-17-demethoxy-geldanamycin (17-AAG) exhibited lower toxicity and improved stability and demonstrated that 17-AAG induces reduction of key regulators of signal transduction in many human tumors, including colon and breast cancer (Usmani and Chiosis 2011;Schulz et al, 2012). In cancer cells, 17AAG binds more strongly to Hsp90, because it is in the form of a heteroprotein complex and in normal cells is mainly homodimeric and this could result in the selective accumulation of it in cancer cells (Usmani and Chiosis 2011).…”

Section: Comparison Of Inhibitory Effects Of 17-aag Nanoparticles Andmentioning

confidence: 99%

Comparison of Inhibitory Effects of 17-AAG Nanoparticles and Free 17-AAG on HSP90 Gene Expression in Breast Cancer

Ghalhar

Akbarzadeh²,

Rahmati³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Inhibiting the HSP90 chaperone destabilizes macrophage migration inhibitory factor and thereby inhibits breast tumor progression

Cited by 21 publications

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Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease

Comparison of Inhibitory Effects of 17-AAG Nanoparticles and Free 17-AAG on HSP90 Gene Expression in Breast Cancer

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