Hsp90 inhibition increases p53 expression and destabilizes MYCN and MYC in neuroblastoma

Abstract

Abstract. Neuroblastoma is a childhood cancer that exhibits either a favorable or an unfavorable phenotype. MYCN and MYC are oncoproteins that play crucial roles in determining the malignancy of unfavorable neuroblastoma. The Hsp90 superchaperone complex assists in the folding and function of a variety of oncogenic client proteins. Inhibition of Hsp90 by small molecule inhibitors leads to the destabilization of these oncogenic proteins and consequently suppresses tumor malignancy. Nonetheless, little is known about the effect of Hsp90 inhibition on the stability of MYCN and MYC proteins. In this study, we investigated the effect of Hsp90 inhibition on the phenotype of unfavorable neuroblastoma cells including its effect on MYCN and MYC expression. Two MYCN-amplified neuroblastoma cell lines (IMR5 and CHP134) and two non-MYCN-amplified cell lines (SY5Y and SKNAS) were used to address the effect of Hsp90 inhibition on the malignant phenotype of neuroblastoma. It was found that Hsp90 inhibition in neuroblastoma cell lines resulted in significant growth suppression, a decrease in MYCN and MYC expression, and an increase in the expression of p53. In the TP53-mutated SKNAS cell line, Hsp90 inhibition enhanced the expression of the favorable neuroblastoma genes EFNB2, . In addition, Hsp90 inhibition reduced HDAC6 expression and enhanced tubulin acetylation. Together our data suggest that Hsp90 inhibition suppresses the growth of neuroblastoma through multiple cellular pathways and that MYC/MYCN destabilization is among the important consequences of Hsp90 inhibition.

Synergistic Activity of Deguelin and Fludarabine in Cells from Chronic Lymphocytic Leukemia Patients and in the New Zealand Black Murine Model

“…Inhibition of c-Myc by deguelin in CLL cells shown in this work is an interesting finding in light of its recently described relevance in the metabolic changes that take place in CLL cells upon contact with their tissue microenvironment, changes that promote CLL cell survival and resistance to chemotherapeutic drugs [ 59 ]. This finding is in agreement with already described inhibition of c-Myc by Hsp90 inhibitors [ 60 , 61 ], and could explain the synergy found between deguelin and fludarabine. Postulated mechanisms explaining this synergy between Hsp90 inhibitors and fludarabine include downregulation of antiapoptotic proteins as a consequence of AKT/NFκB inhibition [ 45 ] or downregulation of DNA repair enzymes and checkpoint regulators that limit the capacity of CLL cells to repair fludarabine-induced DNA damage [ 61 ].…”

“…This finding is in agreement with already described inhibition of c-Myc by Hsp90 inhibitors [ 60 , 61 ], and could explain the synergy found between deguelin and fludarabine. Postulated mechanisms explaining this synergy between Hsp90 inhibitors and fludarabine include downregulation of antiapoptotic proteins as a consequence of AKT/NFκB inhibition [ 45 ] or downregulation of DNA repair enzymes and checkpoint regulators that limit the capacity of CLL cells to repair fludarabine-induced DNA damage [ 61 ]. According to our results, both AKT/NFκB inhibition and reinforcement of fludarabine-induced DNA damage take place in degluelin plus fludarabine treated CLL cells, and likely cooperate in induction of apoptosis.…”

GOLPH3 Promotes Cancer Growth by Interacting With STIP1 and Regulating Telomerase Activity in Pancreatic Ductal Adenocarcinoma

“…STIP1 has been reported to be overexpressed in PDAC cell lines and malignant tissue samples from patients with PDAC (27). STIP1 is proposed as a co-chaperone of HSP90 that regulates c-Myc expression in cancerous cells (34). It is reported that c-Myc interacts with an E-box in the hTERT promoter resulting in expression of hTERT and telomerase (35).…”

“…The BiFC assay provided evidence that GOLPH3 interacts with STIP1 and heat shock protein group including HSP90 (Figure 1C). As a 60kDa protein that belonging to one of the co-chaperones families, STIP1 reversibly binds to the protein chaperones HSP90, which regulates c-Myc expression in cancerous cells (33,34). c-Myc activates hTERT transcription via E-box binding, resulting in direct regulation of telomerase activity (35).…”

ABT199/venetoclax synergism with thiotepa enhances the cytotoxicity of fludarabine, cladribine and busulfan in AML cells

“…Addition of a BCL-2 inhibitor such as ABT199/venetoclax thus presumably facilitated the commitment of the tumor cells to undergo apoptosis. The efficacy of such drug combinations is further shown by the cleavage of HSP90 and decreased level of c-MYC, two pro-survival proteins ( Figure 2A ) [ 37 , 38 ].…”