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ic analysis, we previously showed that MIF depletion activates the p53 pathway . Thus, we hypothesized that p53 activation might be a major determinant responsible for the delayed tumor progression and extended survival of MIF/ErbB2 mice. To test this notion, all ErbB2 tumors were natural product library analyzed for p53 levels by immunoblots. Indeed, the majority of MIF/ErbB2 tumors showed significant p53 accumulation, compared with only 21% of MIF+/+ErbB2 tumors . Furthermore, almost all tumors in this p53 activated MIF/ group showed concomitant induction of the p53 target genes p21 and MDM2 , compared with only 28% of MIF+/ tumors. We sequence confirmed the WT status of accumulated p53 in 11 of 11 MIF/ tumors with high p53 levels. No tumor showed Puma activation , consistent with all the absence of apoptosis in this tumor type.
In sum, these data indicate that MIF can be a significant tumor promoter in ErbB2 driven breast cancer in vivo. Even more importantly, natural product library the results also predict that pharmacologic MIF suppression through HSP90 inhibition may have meaningful anti tumor effects within the animal. Hsp90 inhibition through systemic 17AAG therapy induces marked growth inhibition in MIF+/+ErbB2 tumors but shows little impact in MIF/ErbB2 tumors To date, 17AAG mediated inhibition of Hsp90 function was shown to attenuate tumor progression in various human cancer xenograft models. Even so, even though correlated with down regulating HSP90 clients like ErbB2, Akt, and androgen receptor , a causal dependence of the 17AAG induced tumor suppression on the reduction of distinct clients has not been verified.
To test regardless of whether 17AAG down regulates aberrantly stabilized MIF and consequently impairs tumor progression in our spontaneous transgenic BIX01294 breast cancers in vivo, we treated MIF+/+ErbB2 and MIF/ErbB2 mice systemically with 60 mg/kg 17AAG or vehicle by intraperitoneal injections 5 d a week for 3 wk. Indeed, fast tumor growth in MIF+/+ErbB2 mice was brought to a total halt in 17AAG treated animals compared with vehicle treated mice and was accompanied by marked drug induced tumor necrosis . Importantly, this dramatic response in MIF+/+ErbB2 tumors was connected with destabilization of elevated MIF levels also as the other HSP90 clients ErbB2 and Akt, as expected . In contrast and as expected, vehicle treated MIF/ErbB2 tumors grew much more slowly as a result of lack of MIF .
Importantly, though, and in contrast towards the robust effect noticed in MIF+/ tumors, 17AAG therapy basically failed to inhibited growth in MIF/ErbB2 tumors , regardless of the fact that ErbB2 and Akt were equally decreased by 17AAG in these tumors . We repeated the 17AAG therapy experiments on further mice starting with larger tumors and preliminary Erythropoietin outcomes suggest that irrespective of tumor size, MIF can be a vital factor in drug response . In contrast to MIF+/ tumors, larger MIF/ tumors again were only slightly responsive to 17AAG therapy and became so only toward the very end of therapy, equivalent to what we saw for smaller tumors . Thus, the intrinsically slower tumor growth of MIF/ tumors doesn't mask or somehow distort the observed 17AAG effects.
In aggregate, the loss or reduction of 17AAGinduced anti tumor efficacy particularly in MIF/ErbB2, but not in MIF+/+ErbB2, BIX01294 tumors indicates that a vital in vivo target of 17AAG is, surprisingly, the tumor promoting client MIF, in conjunction with all the coexpressed ErbB2 and Akt clients. Conversely, the dramatic anti tumor effect of 17AAG therapy in MIF+/+ErbB2 mice is also the result of MIF degradation. In sum, these data further assistance the notion that MIF can be a pathologically natural product library essential HSP90 client involved in cancer progression and that tumor connected MIF accumulation sensitizes to a 17AAG induced anti tumor response. DISCUSSION Here, we determine MIF as a novel client of the tumor activated HSP90 chaperone machinery and show that HSP90 is responsible for the aberrant MIF accumulation that characterizes several established human cancers.
Furthermore, we show that MIF overexpression BIX01294 in tumor tissues is an essential factor in tumor progression since natural product library mice with MIF deficient ErbB2 driven breast cancer exhibit delayed tumor progression and prolonged survival. Together, these findings render MIF as a druggable anti tumor target. Most importantly, our genetic MIF ErbB2 analysis indicates that induced degradation of MIF, additionally to induced degradation of HSP90 clients from the ErbB2 Akt along with other signal transduction pathways, BIX01294 can be a vital determinant within the growth suppressive anti tumor response to pharmacological HSP90 inhibitors in vivo. Analysis throughout the previous decade established that aberrantly stabilized MIF is an essential tumor promoter with pleiotropic actions in several pathways. Hence, varying degrees of increased MIF levels are identified in a majority of human malignancies , producing MIF an desirable drug target for anti cancer therapy. Even so, our present knowledge of functional interactions of MIF in cancer r