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.

Novel Immune-Related Gene Signature for Risk Stratification and Prognosis of Survival in Lower-Grade Glioma

“…In term of HSP70, encoded by HSPA1B, has emerged as a promising antitumor target in various cancer. Recently, it is also revealed that HSP70 may serve as a diverse immunoregulatory factors by acting as a cytokine in antigen presentation, DC maturation, the activities of NK cells, and myeloid-derived suppressor cells (Jego et al, 2019). Correspondingly, it was illustrated that upregulation of HSPA1B was associated with poor outcomes in hepatocellular carcinoma (Yang et al, 2015).…”

“…On the contrary, increased abundance of M1-type macrophages, and CD8 + T cells were associated with favorable survival outcomes. As mentioned above, the six risk genes can not only have intrinsic roles in tumor growth and apoptosis (i.e., Guo and Dixon, 2016;Chen et al, 2019;Jego et al, 2019), but also serve as the immune-regulatory factors via antigen-presenting cells (APCs) and effector T lymphocytes (Borrego et al, 2006;Surmann et al, 2015;Ling et al, 2017;Zhu et al, 2018;Chen et al, 2019;Wu et al, 2019). Hence, it is worthwhile to explore the relationship between the risk groups and infiltrative immune cells in primary LGG.…”

Targeting STAT3 and STAT5 in Cancer

“…Different animal species can also provide additional mechanistic insights into STAT evolution and the signaling cascades [38]. For instance, understanding STAT activation in the context of heat shock proteins (HSPs) is critical for their involvement in cellular stress and the immune response which was explored by Jego et al [39].…”

Heat Shock Proteins and PD-1/PD-L1 as Potential Therapeutic Targets in Myeloproliferative Neoplasms

“…The strong relationship between the JAK/STAT signaling pathway and HSPs was recently reviewed by Jego et al [ 33 ]. The authors showed that most HSPs can be regulated by STAT proteins both in stress and non stress situations such as heat shock response [ 34 ], adaptation to reactive oxygen species [ 35 ], cell growth, and in response to many other stimuli [ 36 , 37 ].…”

“…The authors showed that most HSPs can be regulated by STAT proteins both in stress and non stress situations such as heat shock response [ 34 ], adaptation to reactive oxygen species [ 35 ], cell growth, and in response to many other stimuli [ 36 , 37 ]. Conversely, HSPs control STAT3/STAT5 activation in cancer [ 33 ]. Based on these observations, it has become obvious that HSPs are of potential interest in MPN.…”