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Review
. 2023 May:211:115505.
doi: 10.1016/j.bcp.2023.115505. Epub 2023 Mar 15.

Heat shock proteins and cancer: The FoxM1 connection

Zahra Alimardan  1 , Maryam Abbasi  2 , Farshid Hasanzadeh  3 , Mahmud Aghaei  4 , Ghadamali Khodarahmi  5 , Khosrow Kashfi  6
Affiliations
Review

Heat shock proteins and cancer: The FoxM1 connection

Zahra Alimardan et al. Biochem Pharmacol. 2023 May.

Abstract

Heat shock proteins (Hsp) and FoxM1 have significant roles in carcinogenesis. According to their relative molecular weight, Hsps are divided into Hsp110, Hsp90, Hsp70, Hsp60, Hsp40, and small Hsps. Hsp70 can play essential functions in cancer initiation and is overexpressed in several human cancers. Hsp70, in combination with cochaperones HIP and HOP, refolds partially denatured proteins and acts as a cochaperone for Hsp90. Also, Hsp70, in combination with BAG3, regulates the FoxM1 signaling pathway. FoxM1 protein is a transcription factor of the Forkhead family that is overexpressed in most human cancers and is involved in many cancers' development features, including proliferation, migration, invasion, angiogenesis, metastasis, and resistance to apoptosis. This review discusses the Hsp70, Hsp90, and FoxM1 structure and function, the known Hsp70 cochaperones, and Hsp70, Hsp90, and FoxM1 inhibitors.

Keywords: Cancer; Cochaperones; FoxM1; Hsp70; Hsp90; Inhibitors.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.
Hsp70s schematic domains. The Hsp70s consist of two high conserved functional domains including an N-terminal nucleotide-binding domain (NBD) and a C-terminal substrate-binding domain (SBD), also an EEVD-motif at C-terminal. The NBD contains the ATP/ADP pocket that binds and hydrolyzes ATP. The SBD contains a substrate-binding pocket that interacts with extended polypeptides as substrate, an α-helical subdomain from the C-terminal side of SBD forms a flexible lid. EEVD-motif participates in binding to cochaperones and other HSPs. Modified and reproduced with permission from [150].
Figure 2.
Figure 2.
A) Hsp70 function cycle for folding protein. B) Hsp70, including Hsp40, BAG1, and CHIP, is used to target selected substrate proteins for ubiquitination and degradation in the proteasome. C) Hsp70/Hsp90 with cochaperones Hsp40, HIP and, HOP, play a main role in folding unfolded proteins. D) Hsp70 with cochaperones Hsp40, CHIP, BAG3 plays a main role in the signaling pathway FoxM1.
Figure 3.
Figure 3.
Chemical structures of: A) C-terminal domain Hsp70 inhibitors. B) ATP-Competitive inhibitors of Hsp70. C) Allosteric inhibitors of Hsp70
Figure 4.
Figure 4.
Crystal structure of Hsp90 dimer (PDB ID: 2CG9). The red dashed circles highlight an ATP-binding pocket. Reproduced from [151], open access.
Figure 5.
Figure 5.
Chemical structures of: A) N-terminal domain Hsp90 inhibitors. B) Hsp90 middle domain inhibitors. C) Hsp90 C-terminal inhibitors.
Figure 6.
Figure 6.
A) FoxM1 Structure bound to DNA (PDB:3G73). B) FoxM1isoform domains.
Figure 7.
Figure 7.
Chemical structures of direct FoxM1 inhibitors such as: Thiostrepton, Honokiol, FDI-6 (R=F) and some derivatives, RCM-1, 1,1-diarylethylene mono and diamines (NB-55, NB-65 and NB-70) and TFI-10.
See this image and copyright information in PMC

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