HSP70/HSF1 axis, regulated via a PI3K/AKT pathway, is a druggable target in chronic lymphocytic leukemia

Abstract

Considering the role played by the heat shock protein of 70 kDa (HSP70) in cancer, we characterized this protein and its major regulator, the heat shock factor 1 (HSF1), in chronic lymphocytic leukemia (CLL). We found both HSP70 and HSF1 overexpressed in CLL patients, correlated to poor prognosis and abnormally localized in the nucleus of leukemic B cells. The two proteins were strictly correlated each other and their levels decreased consensually in those patients responding to in vivo therapeutic regimens. HSP70 and HSF1 inhibition was proved to be effective in inducing a dose-dependent in vitro apoptosis of CLL B cells. Considering that HSF1 is finely regulated by kinases belonging to pathways triggered by rat sarcoma (RAS), we benefited from a previous proteomic study performed in CLL patients aiming to assess the activation/expression of key signaling proteins. We found that patients showing high levels of HSP70 also expressed high Akt-Ser473, thus activating HSF1. Inhibition of PI3K, which activates AKT, reduced the expression of HSF1 and HSP70. By contrast, HSP70-low patients displayed high activation of MEK1/2 and ERK1/2, known to negatively regulate HSF1. These data demonstrate that the HSP70 expression is regulated by the modulation of HSF1 activity through the activation of RAS-regulated pathways and suggest the HSP70/HSF1 interplay as an interesting target for antileukemic therapies. Finally, inhibition of PI3K, that activates AKT, reduced the expression of HSF1 and HSP70.

miR-30b-3p Inhibits Proliferation and Invasion of Hepatocellular Carcinoma Cells via Suppressing PI3K/Akt Pathway

“…It was reported that TRIM27 promoted EMT through activation of p-Akt in colorectal cancer . The PI3K/Akt signalling pathway is one of the well-characterised pathways in cancer progression (Frezzato et al, 2019). To determine whether miR-30b-3p could affect PI3K/Akt signalling, we first observed that the protein levels of TRIM27 and p-Akt were both highly expressed in HCC tissues compared with non-carcinoma tissues ( Figure 6A), indicating that PI3K/Akt signalling might be activated when TRIM27 is overexpressed HCC tissues.…”

In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment

“…The sub-cellular fractions were obtained using a commercial kit (Thermo Scientific, Rockford, IL, USA) using detergents which could separate cytoplasmic, membrane and nuclear proteins [54]. 10 7 lymphocytes were centrifuged and incubated with different buffers following manufacture's protocol.…”

In vitro maturation in the presence of Leukemia Inhibitory Factor modulates gene and miRNA expression in bovine oocytes and embryos

“…This likely reflects large-scale turnover of maternally derived mRNA as embryos advance through development 72 . However, in vitro maturation with LIF increased HSPA1A expression in expanded blastocysts, possibly through activation of PI3K-AKT pathway by LIF and increased HSPA1A transcription 73 . We postulate that LIF may help suppress apoptosis through this pathway.…”