Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy

Abstract

While cells from multicellular organisms are dependent upon exogenous signals for their survival, growth, and proliferation, commitment to a specific cell fate requires the correct folding and maturation of proteins, as well as the degradation of misfolded or aggregated proteins within the cell. This general control of protein quality involves the expression and the activity of molecular chaperones such as heat shock proteins (HSPs). HSPs, through their interaction with the STAT3/STAT5 transcription factor pathway, can be crucial both for the tumorigenic properties of cancer cells (cell proliferation, survival) and for the microenvironmental immune cell compartment (differentiation, activation, cytokine secretion) that contributes to immunosuppression, which, in turn, potentially promotes tumor progression. Understanding the contribution of chaperones such as HSP27, HSP70, HSP90, and HSP110 to the STAT3/5 signaling pathway has raised the possibility of targeting such HSPs to specifically restrain STAT3/5 oncogenic functions. In this review, we present how HSPs control STAT3 and STAT5 activation, and vice versa, how the STAT signaling pathways modulate HSP expression. We also discuss whether targeting HSPs is a valid therapeutic option and which HSP would be the best candidate for such a strategy.

Keywords: chaperones; heat shock proteins; stabilization; targeted therapy.

Figure 1

Localization and described functions of HSP90 within the STAT3 and STAT5 signaling pathways. HSP90 promotes those pathways through direct interaction with STAT3 or STAT5 dimers and favors their phosphorylation, nuclear localization, and promoter binding, but HSP90 also limits dephosphorylation and proteasomal degradation. Upstream of STAT3/STAT5 activation, HSP90 stabilizes several kinases, like JAK2, JAK2^V617F, c-Src, v-Src, ACK1, BCR-ABL, EML4-ALK, Lck^Y505F, and HCK^499F, and several receptor tyrosine kinases, such as the ErbB family.

Figure 2

Structure of the main HSP90 inhibitors. The inhibitors targeting the ATP binding site at the N-terminus and the C-terminus of HSP90 are depicted in green and orange, respectively.

Figure 3

Localization and described functions of HSP27 within the STAT3 and STAT5 signaling pathways. HSP27 state of oligomerization varies dynamically to modulate its binding capacity to target proteins in a context-dependent way. HSP27 directly interacts with pYSTAT3 and total STAT3 to promote stabilization and phosphorylation. HSP27 directly binds to JAK2^V617F/STAT5 complexes to prevent STAT5 dephosphorylation by SHP-2 in MPN. HSP27 also displaces multiprotein complexes like the STAT3/PKR complex.

Figure 4

Localization and described functions of HSP110 and HSP70 within the STAT3 and STAT5 signaling pathways. HSP110 directly binds to STAT3 in the cytosol and favors its phosphorylation through JAK2, and, through this mechanism, participates in the promotion of cell proliferation. HSP110α and HSP110β localize to the cytoplasm and nucleus of cells, respectively. HSP110β induces the expression of HSP70 in mammalian cells. Overexpression of HSP110β stimulated the phosphorylation of STAT3 (Tyr705) and its translocation to the nucleus. STAT3 binds to the sequence of the HSP70 promoter at the level of a sequence (−206 to −187 base pair) whose mutation abrogated the activation of the HSP110β-mediated HSP70 promoter. HSP70 directly interacts with STAT3 and STAT5. It favors STAT3 phosphorylation and activity, and STAT5 levels, phosphorylation, and activity.

Figure 5

Structure of the main small-molecule inhibitors of HSP27 (blue), HSP70 (Green), and HSP110 (Orange). RP101 can inhibit HSP27 function via direct binding to Phe29 and Phe33. VER-155008 binds to the ATP-binding site at the N-terminus of HSP70. Pifithrin-µ inhibits specifically function of HSP70 via direct binding to its substrate binding domain. Compounds 52 and 33 bind to the ATP binding site at the N-terminus of HSP110.