HSP70 and Its Targeting in Onco-Hematological Diseases

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1		Federica Frezzato	--	3439	2023-04-20 13:28:04	\|
2	format	Jason Zhu	Meta information modification	3439	2023-04-21 07:51:20	\|

This entry is adapted from the peer-reviewed paper 10.3390/biom13040604

The search for molecules to be targeted that are involved in apoptosis resistance/increased survival and pathogenesis of onco-hematological malignancies is ongoing since these diseases are still not completely understood. A good candidate has been identified in the Heat Shock Protein of 70kDa (HSP70), a molecule defined as “the most cytoprotective protein ever been described”. HSP70 is induced in response to a wide variety of physiological and environmental insults, allowing cells to survive lethal conditions. This molecular chaperone has been detected and studied in almost all the onco-hematological diseases and is also correlated to poor prognosis and resistance to therapy.

Heat Shock Proteins HSP70 leukemia lymphoma

1. Introduction

While in normal cells Heat Shock Protein of 70kDa (HSP70) has been demonstrated to assist in a plethora of mechanisms to safeguard the cell from damage and allow it to survive, in cancer cells the same characteristics are devoted to the maintenance of the tumoral cell life and spreading, making HSP70 fit all the hallmarks of cancer ^[1]. In fact in cancer cells, HSP70 takes a place in many anti-apoptotic pro-survival pathways ^[2], i.e., HSP70 binds to DR4/5 (death receptor 4 and 5) ^[3], binds Bax ^[4], blocks JNK activity ^[5], stops the recruitment of pro-caspase 9 to the apoptosome ^[6], prevents the release to the cathepsins ^[7]^[8], etc. HSP70 is frequently aberrantly expressed in many solid tumors, as well as hematological malignancies with prognostic and therapeutic implications. HSP70 is largely expressed in hematological malignancies, including lymphoid diseases and chronic or acute myeloid leukemias, often associated with bad prognosis ^[9].

2. Acute and Chronic Leukemias

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease bearing different clinical as well as biological features. The disease is characterized by the proliferation and the accumulation of lymphoid-lineage immature cells in the bone marrow, peripheral blood, lymphoid tissues and other compartments ^[10]. Acute myeloid leukemia (AML) is a clonal proliferation of hematopoietic stem cells, characterized by blocked or severely impaired differentiation and progressive accumulation of blasts in various stages of maturation ^[11]. Chronic myeloid leukemia (CML) is a chronic myeloproliferative disorder affecting the hematopoietic stem cell characterized by a leukocytosis of variable degree ^[12].

In 1992, the expression level of HSP70 was examined in cells from AML patients and demonstrated that the HSP70 protein was expressed in these cells, also in the absence of heat shock ^[13]. Later, the expression of HSPs was analyzed in permeabilized leukemic cells from both AML and CML patients by flow cytometry and showed that HSPs’ expression was significantly increased in AML versus CML ^[14]. Afterwards, the susceptibility to apoptosis of AML cells in vitro was correlated with intracellular expression of HSP70 and it was paradoxically observed that AML cells which expressed high levels of HSP70 were more prone to apoptosis ^[15]. Since the 2000s, a role has also been assigned for the form of HSP70 localized on the cell surface as a recognition signal for NK (natural killer) cytotoxic cells. It has been demonstrated, in fact, that HSP70^pos AML cells are killed by NK cells stimulated with low doses of IL-2 plus recombinant HSP70. Moreover, the investigation of the stimulation capacity of the TKD peptide (see 1.2) using PBMCs derived from AML patients as effector, and bone marrow-derived leukemic blast (HSP70^pos) as target cells, indicated that membrane-bound HSP70 provides a target structure for TKD-activated PBMCs. Another piece of evidence resides in the fact that HSP70^pos K562 cells represent an activating ligand for IL-2/TKD-activated NK effector cells ^[16]^[17]^[18]. HSP70 membrane expression has also been associated with worse AML prognosis ^[19]. The plasma-circulating HSP70 was demonstrated to have a role in anti-tumor immune responses and its levels may reflect the severity of the disease. In AML and ALL patients, the HSP70 levels found in the plasma were significantly higher as compared to those in healthy controls, also being significantly correlated with lactate dehydrogenase (LDH) expression and white blood cells’ (WBC) counts, thus reflecting the overall tumor load ^[20]. Anti-HSP70 antibody and its antigen concentrations in the peripheral blood of AML patients were also evaluated to assess the utility of this determination, thus finding significantly higher anti-HSP70 antibody concentration compared to the control group. Patients who presented high levels of antigen but low levels of anti-HSP70 antibody had significantly shorter overall survival (OS) thus suggesting that the use of anti-HSP70 antibodies and HSP70 antigen could be valuable indicators of adverse prognosis in AML ^[21]. Still, in AML, high expression of HSPA8 (that codes for the constitutive form of HSP70) has been observed to be associated with adverse clinical outcomes, this gene being identified as a potential marker for shorter OS in AMLs bearing a normal karyotype ^[22]. Several works have also been dedicated to the forms of HSP70 residing in particular cell compartments such as GRP78 of the endoplasmic reticulum or GRP75 in the mitochondrion. As a key component of the pro-survival axis of the unfolded protein response (UPR), GRP78 is highly expressed in relapsed B-lineage ALL, contributing to chemotherapy resistance of leukemic B-cell precursors ^[23]. In this context, literature data demonstrated an unrecognized vulnerability of pre-B cell-derived ALL cells to genetic or pharmacological inhibition of the UPR pathway thus establishing a mechanistic rationale for the treatment of children with pre-B ALL with agents that block the UPR pathway and induce ER stress ^[24]. In an effort to better characterize high- and standard-risk pediatric B-ALL patients at diagnosis, a study explored the role of surface (s) GRP78, thus reporting a distinctive cluster containing high levels of sGRP78, CD10, CD19, and CXCR4 in bone marrow samples obtained from high-risk patients. Moreover, circulating lymphoblastic leukemia cells were shown to express sGRP78 and CXCR4 ^[25]. Although upregulation of HSP70 has been demonstrated to be involved in tumor development in ALL, the molecular mechanism of HSP70 in ALL remains unclear. Guo et al. recently demonstrated that HSP70 is induced in leukocytes and monocytes from the blood of ALL patients and its suppression enhances apoptosis and inhibits cell proliferation by suppressing TAK1 and inducing Egr-1 ^[26]. In B- and T-leukemia cell lines, HSP70 is induced both at the cell surface and in the cytoplasm by anti-CD99 antibody, where this receptor is involved in various intracellular and extracellular processes such as adhesion, migration and apoptosis ^[27]^[28]^[29]. CD99 ligation enhances HSP70 transcription in ALL cells ^[30]. Different authors over the years have assigned to HSP70 a role as a potential therapeutic target and in reversing drug-resistance. Different strategies for targeting HSP70 have been proposed as monotherapy or in combination, especially with HSP90 inhibitors (i.e., 17-AAG or 17-DMAG). With regard to the latter statement, data from literature indicate that HSP70 induction attenuates the apoptotic effects of 17-AAG and, on the other hand, abrogation of HSP70 significantly enhances the anti-leukemia activity of 17-AAG ^[31]^[32]. Kaiser et al. investigated the in vitro anti-leukemic effects of pifithrin-μ, an inducible HSP70 inhibitor, in AML and ALL cell lines and in primary AML blasts, demonstrating that pifithrin-μ was effective in inhibiting cell viability at micromolar concentrations ^[33]. Moreover, in AML using VER-155008, a dose-dependent inhibition of cytokine-dependent AML cell proliferation and a pro-apoptotic effect have been demonstrated, this effect being enhanced in combination with HSP90 inhibitors ^[34]. Another study provided evidence that the xanthone beta-mangostin is effective in inducing apoptosis in the promyelocytic leukemia HL60 cell line, upregulating p53 and Bax and suppressing Bcl-2 and HSP70 genes in addition to arresting the cell cycle in vitro ^[35]. Another natural compound, parthenolide, targets HSP70, thus inducing heat shock response in THP-1 leukemia cells ^[36]. In 2021, Hu et al. discovered a novel HSP70 inhibitor with potent anti-tumor efficacy, named QL47, showing that HSP70 targeting might be a promising therapeutic method for the treatment of FLT3-ITD-positive AML, potentially able to overcome drug-resistance ^[37]. Since proteasome has been validated as a target of cancer therapeutics, the deubiquitinase (DUB) inhibitor VLX1570 was characterized in ALL at both UPR and protein translation levels. VLX1570 induced accumulation of polyubiquitinated proteins and increased expression of the chaperone GRP78 in ALL cells and also induced cleavage of PARP, meaning it induced apoptosis ^[38]. The same compound was demonstrated to have a potential anti-leukemic effect through the generation of ROS and induction of ER stress in both myeloid and lymphoid leukemia cell lines ^[39]. Thanks to CAR-T technology, a CAR-T directed against GRP78 found on AML blasts’ surface has been developed. GRP78-CAR T cells sequentially kill tumor cells and secrete cytokines with a potent anti-AML activity in vivo, this effect being improved by the Src kinases inhibitor Dasatinib ^[40]. In another study, the immunogenicity of AML and ALL cells was enhanced by transfection with the HSP70 gene of BCG (Bacille Calmette–Guérin). Short-term culture of those leukemia cells exhibited an increased number, no change in antigen expression, and enhanced immunogenicity with beneficial anti-leukemia effects ^[41]. Strategies indirectly targeting HSP70 have also been explored. CX-4945, the highly specific orally available ATP-competitive inhibitor of CK2α, induces apoptosis in T-ALL cell lines and T-lymphoblasts from patients. CX-4945 affects the UPR, as demonstrated by a significant decrease in the levels of GRP78 thus leading cells to apoptosis ^[42].

3. Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by the accumulation of small mature B lymphocytes due to both increased proliferation and defects in apoptotic mechanisms ^[43]. In 2010, a study investigated the localization of different HSPs (including HSP70) in B cells from patients with CLL and age-matched healthy subjects. Patients were found to differently express very high or very low levels of both sHSP70 and intracellular (i) HSP70 in CD5⁺/CD19⁺ neoplastic cells, although surface and intracellular datasets did not correlate. Levels of circulating HSP70 were found to be correlated with intracellular levels of HSP70 and were also found to be significantly lower in patients undergoing corticosteroid-containing regimens ^[44]. Moreover, GRP78 has been found to be expressed on the surface of CLL cells and associated with sMIC-A, a molecule which impairs NKG2D-mediated cytotoxicity ^[45]. Another study demonstrated that both lymphocytes and monocytes from CLL, and also from chronic myelomonocytic leukemia (CMML), showed high levels of total HSP70 expression versus healthy subjects, the majority of HSP70 in these tumors was determined to be expressed at the cell surface ^[46]. In CLL, it has been proposed that a combination of sub-lethal doses of chemotherapeutic agents and membrane fluidizing treatments, enhances drug efficacy and apoptosis in vitro. The treatment also resulted in a significant contemporary decrease in iHSP70 and increase in sHSP70, this localization affecting the cytotoxicity of doxorubicin ^[47]. The “molecular machine” HSP70, which inhibits cell death by stopping the recruitment of procaspase-9 to the Apaf-1 apoptosome, was found overexpressed in CLL cells following an RPPA (Reverse Phase Protein Array) study . In that manuscript, a group demonstrated a correlation between HSP70 levels and the response to chemo-immunotherapy (i.e., fludarabine and cyclophosphamide + rituximab or bendamustine + rituximab) in CLL. Beside HSP70 itself, the role of its co-chaperone BAG3, has been characterized in CLL. Chen and colleagues showed that BAG3 mRNA levels were significantly higher in CLL than in healthy controls, with BAG3 levels in the drug-resistant group higher, as compared with the drug-responsive group ^[48]. The role of the BAG3 protein in leukemia cell survival and response to therapy has been reviewed in ^[49]. The mechanism of BAG3 in CLL has been addressed in Zhu et al. ^[50], this highlighting that patients with higher BAG3 levels have a worse OS in ZAP-70 positive and p53 negative subgroups. Moreover, BAG3 has been demonstrated to inhibit cell apoptosis in primary CLL cells and its knock-down inhibited CLL cell migration. Recently, a study has been aimed at evaluating the effect of metabolic factors involved in invasive CLL on apoptotic factors. The obtained results showed a strong association among the expression of BAG3, GRP78 and HIF-1α with patients’ stages, highly correlated with their expression rate (both gene and protein). The increased expression of GRP78 and HIF-1α resulted in a BAG3 increase, as well as in disease progression ^[51].

4. Multiple Myeloma

Multiple Myeloma (MM) is a neoplastic disease involving plasma cells which proliferate and expand in the hematopoietic marrow and represent the cause of the typical multiple osteolytic lesions. Monoclonal plasma cells produce immunoglobulins, identical to each other, which migrate homogeneously during protein electrophoresis thus forming the characteristic monoclonal peak ^[52]. The first evidence of HSP70 research in MM was reported in 1989 when GRP78 was identified as the immunoglobulin heavy-chain-binding protein and was found expressed at a high level in the myeloma B-cell line NS-1 ^[53]. For other works concerning HSP70 in MM researchers had to wait for the first years of the twenty-first century. In those years, HSP70 inhibition has been demonstrated to reverse cell adhesion mediated- and acquired-drug resistance in MM. In MM cell lines and primary plasma cells, a role for HSP70 in the development of chemo-resistance was demonstrated through its enhanced expression after MM cells adhesion to both bone marrow stromal cells and fibronectin. Inhibition of HSP70 reduced adhesion, causing apoptosis of both acquired and de novo drug-resistant MM cells ^[54]. In the same context, later, GRP78 knock down was demonstrated to trigger dramatic changes in MM PC3 cell line morphology, thus decreasing their adhesion to osteoblasts and this dependent, at least in part, on a reduced N-cadherin expression ^[55]. In another study, beyond its own features, soluble HSP70 has been evaluated as a potential good biomarker of HSP90 inhibition as an alternative to cytosolic HSP70 ^[56]. As well as for other hematological diseases, inhibition of HSP70 (i.e., with triptolide and KNK437) in MM has been assessed to counteract the side effects of HSP90 inhibition and to enhance the apoptosis induced by it ^[57]. HSP72/73 were found to be overexpressed in MM and their knockdown or treatment with VER-155008 induced apoptosis of myeloma cells associated with a decreased protein level of HSP90-chaperone clients known to affect several oncogenic signaling pathways. Moreover, HSP70 knockdown/inhibition worked synergistically with the HSP90 inhibitor NVP-AUY922 in affecting myeloma cells’ viability ^[58]. The HSP70 inhibitor VER-155008 was used in combination with Bortezomib, this combination being demonstrated to induce a synergistic and remarkable MM cell apoptosis in vitro ^[59]. More recently, HSF1, the master regulator of HSP70, has been introduced as a possible therapeutic target (see also Section 3.2). Heimberger and colleagues reported that HSF1 is frequently overexpressed in INA-6 and MM.1S myeloma cell lines. HSF1 knockdown or its downregulation by triptolide, induces apoptosis in MM cell lines and in primary MM cells ^[60]. Moreover, HSF1 inhibition by KNK-437 in combination with bortezomib has been demonstrated to play additive effects on apoptosis induction in cells belonging to MM patients with poor prognosis ^[61]. A member of non-ATP-site inhibitors of HSP70, MAL3-101, has been examined for its anti-myeloma effect, thus discovering its pro-apoptotic function in MM cell lines in vitro and in vivo in a xenograft plasmacytoma model, as well as on primary tumor cells and bone marrow endothelial cells from myeloma patients. In addition, this inhibitor combined with the proteasome inhibitor MG-132, significantly potentiated its anti-myeloma effect ^[62]. Another piece of evidence that the targeting of HSP70 represents a good therapeutic approach which may be effective in the treatment of MM, was highlighted in L. Zhang et al. ^[63]. They demonstrated that the silencing of HSP70 increased Ig retention, decreased the ubiquitination required for proteasome degradation, and triggered multiple cellular responses (i.e., CDK4, C-RAF, HSF1, GRP78, LAMP-2A, and caspase-3) thus contributing to MM cell death. Moreover, VER-155008 was used alone or in combination with the HSP90 inhibitor 17-AAG. Again, the effects of VER-155008 in combination with bortezomib have been studied by Eugênio and colleagues ^[64]. A further HSP70 inhibitor, PET-16, was tested and it was found to induce apoptosis in MM cell lines at low micromolar doses (different from normal cells) also causing proteotoxic stress ^[65]. Treatment of myeloma cells with bortezomib increased GRP78 levels and activated GRP78-dependent autophagy. In particular, cells resistant to bortezomib showed a significantly upregulated GRP78. Co-treatment with metformin, an anti-diabetic agent, was demonstrated to suppress GRP78 and to enhance the pro-apoptotic effect of bortezomib ^[66]. Another study concluded that MM cells resistant to bortezomib treatment display a GRP78^high/p21^high/CDK6^low/P-Rb^low profile, these markers identifying quiescent cells able to fuel a subsequent recurrence ^[67]. GRP78 is an appealing candidate for immunotherapeutic intervention as it is overexpressed at all myeloma stages and increased in patients with disease progression, especially in those patients with drug-resistance and extramedullary disease. The use of dexamethasone, PAT-SM6 (monoclonal antibody against sGRP78), and lenalidomide showed synergistic anti-MM effects in proliferation assays ^[68]. The role of GRP78 as a potential novel biomarker and/or therapeutic target in MM has been recently reviewed in Ninkovic et al. ^[69]. The immunomodulatory action of HSP70 has been recently highlighted since HSP70^pos exosomes are primarily found in the bone marrow of MM patients, contributing to IFNγ production and thus suggesting they play a crucial immunomodulatory action in the tumor microenvironment ^[70]. Another group found that the hDKK1–hHSP70 fusion vaccine could significantly suppress tumor growth of murine MM. A significant decrease in proliferation and an increase in apoptosis were also observed in the tumor tissues injected with the hDKK1–hHSP70 vaccine, demonstrating that xenogeneic homologous vaccination had great immunogenicity ^[71]. More recently, a decrease in HSP70 expression has been found in MM cells treated with a combination of gemcitabine + busulfan + melphalan + panobinostat + venetoclax (anti-Bcl-2) ^[72]. Allosteric HSP70 inhibitors, named JG compounds, have also been explored as myeloma therapeutics. They impact myeloma proteostasis by destabilizing the 55S mitoribosome thus suggesting JGs have the most prominent anti-myeloma effect through mitochondrial-localized HSP70 (i.e., GRP75) rather than through the inhibition of cytosolic HSP70 ^[73]. A very recent work identifies HSP70 family members as the “managers” of the molecular network of the proteasome machinery, except for controlling Nrf1/2. These results indicate the combination of HSP70 and Nrf1/2 inhibitors as promising therapeutic targets in MM ^[74].

5. Lymphomas

5.1. Diffuse Large B-Cell Lymphoma

A proteomic study, with subsequent validation, identified GRP78 as differentially expressed in non-GC (germinal center, higher expression) as compared to GC-DLBCL (diffuse large B-cell lymphoma) ^[75] thus highlighting the importance of this protein in lymphoma as well as in leukemia (see previous paragraphs). GRP78, in fact, is related to worse OS of DLBCL patients as well as related to bortezomib-resistance in DLBCL cell lines ^[76]. In activated B cell-like (ABC)-DLBCL, a common subtype of aggressive lymphoma typically refractory to therapies, an N-terminal misfolding mutation renders Blimp-1 (B lymphocyte-induced maturation protein-1) unstable. It has been demonstrated that HSP70 selectively escorts mutant Blimp-1 proteins to Hrd1 that, in turn, sequesters mutant Blimp-1 for cytoplasmic degradation. HSP70 inhibition (by VER155008) restores the function of mutant Blimp-1 and suppresses the growth of ABC-DLBCL xenografts ^[77]. In A20 and BL3750 lymphoma tumors in mice, the increased efficacy of accelerated local tumor irradiation was correlated with higher levels of tumor cell necrosis versus apoptosis and expression of “immunogenic cell death” markers, including HSP70 ^[78]. Recently, GRP75 was found to be highly expressed and correlated with resistance to rituximab-based therapy and poor survival in patients with DLBCL. In a mouse model, genetic depletion of GRP75 increased the activity of Rituximab indicating GRP75 is a novel target for the treatment of DLBCL ^[79].

5.2. Mantle Cell Lymphoma

In 2013, the rise of HSP70 protein expression was highlighted in mantle cell lymphoma (MCL) as the reflection of the degree of cellular proteotoxic stress caused by the association of bortezomib plus CK2 inhibitors (i.e., CX-4945) in MCL cell lines ^[80]. Sehikara and colleagues proposed the simultaneous inhibition of XPO1 (nuclear transporter exportin-1) and mTOR signaling as a promising tool targeting pro-survival metabolism in MCL, this strategy inhibiting c-Myc, HSF1 and its target HSP70 ^[81]. Moreover, it has been demonstrated that MCL cells are sensitive to p97 inhibitors in vitro whose combination with HDAC6 inhibitors induces synergistic apoptosis by inducing the ER stress marker GRP78 ^[82].

5.3. Hodgkin’s Lymphoma

HSP70 was also studied in patients with Hodgkin’s Lymphoma (HL) by an avidin–biotin immunoperoxidase complex technique, where staining resulting in HSP70 expression was found in 85% of the HL examined and the frequency of HSP70 positive cases was significantly higher than that of HSP70 negative cases. The association between HSP70 expression and HL thus appeared to be more frequent in patients with LD (lymphocyte depleted) and NS (nodular sclerosing) subtypes, although examples of HSP70-positive tumors were found in all histological subtypes ^[83]. HSC70 and HSP72 expression in HL, infected or not by Epstein–Barr virus (EBV) was also analyzed by the immunoperoxidase method in paraffin sections and demonstrated no differences according to clinical stage, treatment response or the presence of EBV. The pathological subtypes with the higher expression in lymphocytes were mixed cellularity and nodular sclerosis ^[84]. Later, using tissue microarrays, it was suggested there was a role for HSP70, and other apoptotic markers, in modulating the apoptosis in classical HL, mainly through the HSP70–HSP40 system, and in the stabilization of p53 ^[85]. As far as the ER counterpart of HSP70, GRP78, is concerned, it has been demonstrated that its expression was increased by LMP1 (latent membrane protein-1) transfection in HL cell lines.

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