HSPs/STAT3 Interplay Sustains DDR and Promotes Cytokine Release by Primary Effusion Lymphoma Cells

Gonnella, Roberta; Arena, Andrea; Zarrella, Roberta; Montani, Maria Saveria Gilardini; Santarelli, Roberta; Cirone, Mara

doi:10.3390/ijms24043933

Cited by 6 publications

(8 citation statements)

References 31 publications

(53 reference statements)

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“…Even if the STAT3 dephosphorylation was slightly further reduced by AZA/AG490 combination compared to AG490, a stronger downregulation of c-Myc, Cyclin D1 and HSP27 was observed ( Figure 2 C). The overexpression of these molecules has been closely correlated with the survival and progression of cancers, including PEL [ 29 , 30 ]. Together, these results suggest that 5-AZA could be a promising strategy to increase the sensitivity of PEL cells to treatment with STAT3 tyrosine inhibitors.…”

Section: Resultsmentioning

confidence: 99%

5-AZA Upregulates SOCS3 and PTPN6/SHP1, Inhibiting STAT3 and Potentiating the Effects of AG490 against Primary Effusion Lymphoma Cells

Di Crosta,

Arena,

Benedetti

et al. 2024

CIMB

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Epigenetic modifications, including aberrant DNA methylation occurring at the promoters of oncogenes and oncosuppressor genes and histone modifications, can contribute to carcinogenesis. Aberrant methylation mediated by histone methylatransferases, alongside histones, can affect methylation of proteins involved in the regulation of pro-survival pathways such as JAK/STAT and contribute to their activation. In this study, we used DNA or histone demethylating agents, 5-Azacytidine (5-AZA) or DS-3201 (valemetostat), respectively, to treat primary effusion lymphoma (PEL) cells, alone or in combination with AG490, a Signal transducer and activator of transcription 3 (STAT3) inhibitor. Cell viability was investigated by trypan blue assay and FACS analysis. The molecular changes induced by 5-AZA and/or AG490 treatments were investigated by Western blot analysis, while cytokine release by PEL cells treated by these drugs was evaluated by Luminex. Statistical analyses were performed with Graphpad Prism® software (version 9) and analyzed by Student’s t test or a nonparametric one-way ANOVA test. The results obtained in this study suggest that 5-AZA upregulated molecules that inhibit STAT3 tyrosine phosphorylation, namely Suppressor of Cytokine Signaling 3 (SOCS3) and tyrosine–protein phosphatase non-receptor type (PTPN) 6/Src homology region 2 domain-containing phosphatase-1 (SHP-1), reducing STAT3 activation and downregulating several STAT3 pro-survival targets in PEL cells. As this lymphoma is highly dependent on the constitutive activation of STAT3, 5-AZA impaired PEL cell survival, and when used in combination with AG490 JAK2/STAT3 inhibitor, it potentiated its cytotoxic effect. Differently from 5-AZA, the inhibition of the EZH1/2 histone methyltransferase by DS-3201, reported to contribute to STAT3 activation in other cancers, slightly affected STAT3 phosphorylation or survival in PEL cells, either alone or in combination with AG490. This study suggests that 5-AZA, by upregulating the expression level of SOCS3 and PTPN6/SHP1, reduced STAT3 activation and improved the outcome of treatment targeting this transcription factor in PEL cells.

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Section: Resultsmentioning

confidence: 99%

5-AZA Upregulates SOCS3 and PTPN6/SHP1, Inhibiting STAT3 and Potentiating the Effects of AG490 against Primary Effusion Lymphoma Cells

Di Crosta,

Arena,

Benedetti

et al. 2024

CIMB

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“…The collaboration between HSPs and STAT3 has been documented in various biological processes. A positive feedback loop involving HSPs and STAT3 assumes a pivotal role in sustaining DNA Damage Response (DDR) and preventing DNA damage in Primary Effusion Lymphoma (PEL) cells [69]. The Stat3 inhibitor, Stattic, impedes the acquisition of thermotolerance by suppressing mild heat shockinduced Stat3 phosphorylation and Hsp105 expression [70], thereby implicating the regulatory influence of STAT3 on Hsp105.…”

Section: Discussionmentioning

confidence: 99%

Conserved mechanisms of self-renewal and pluripotency in mouse and human ESCs regulated by simulated microgravity using a 3D clinostat

Ye,

Xie,

et al. 2024

Cell Death Discov.

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Embryonic stem cells (ESCs) exhibit unique attributes of boundless self-renewal and pluripotency, making them invaluable for fundamental investigations and clinical endeavors. Previous examinations of microgravity effects on ESC self-renewal and differentiation have predominantly maintained a descriptive nature, constrained by limited experimental opportunities and techniques. In this investigation, we present compelling evidence derived from murine and human ESCs, demonstrating that simulated microgravity (SMG)-induced stress significantly impacts self-renewal and pluripotency through a previously unidentified conserved mechanism. Specifically, SMG induces the upregulation of heat shock protein genes, subsequently enhancing the expression of core pluripotency factors and activating the Wnt and/or LIF/STAT3 signaling pathways, thereby fostering ESC self-renewal. Notably, heightened Wnt pathway activity, facilitated by Tbx3 upregulation, prompts mesoendodermal differentiation in both murine and human ESCs under SMG conditions. Recognizing potential disparities between terrestrial SMG simulations and authentic microgravity, forthcoming space flight experiments are imperative to validate the impact of reduced gravity on ESC self-renewal and differentiation mechanisms.

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“…Several HSPs play a role in the stability of the molecules involved in DNA repair [8,9]. Here, we explored the impact of HSP110 inhibition on DNA damage and observed that γH2AX-positive foci increased in BC3 and BCBL-1 silenced cells (Figure 3A), suggesting that the reduction in this HSP induced DNA damage.…”

Section: Hsp110 Knockdown Induces Dna Damage By Impairing Hr and Nhej...mentioning

confidence: 95%

“…We have recently reported that several HSPs, including HSP27, HSP70, and HSP90, overlap in their capacity to sustain the stability of several DDR molecules in PEL cells, contributing, also for that reason, to the survival of this aggressive B cell lymphoma. Moreover, in the above-mentioned study, we reported that the inhibition of these three HSPs inhibited STAT3 phosphorylation and reduced pro-inflammatory cytokine release, which may not only affect the survival of cancer cells but also contribute to shaping the tumor microenvironment [9]. Among the HSPs, one of the less studied is HSP110, a holdase chaperone, considered a non-canonical HSP70 protein.…”

Section: Introductionmentioning

confidence: 99%

“…HSP inhibition might therefore represent a promising strategy to specifically target cancer cells, while sparing normal cells that express a low level of these molecules and less intensely rely on them for cell survival. Among the numerous functions of HSPs, they may stabilize oncogenes, such as c-Myc [3] and mutp53 [4,5], and chaperone kinases involved in the activation of oncogenic pathways such as NFkB [6] and STAT3 [7] or sustain the expression of molecules involved in the DNA damage response (DDR) [8,9], which is essential to preserve genome integrity. Ours and others' laboratories have shown that STAT3, a molecular pathway activated by IL-6, released by PEL cells, and via the expression of several viral proteins, plays a crucial role in sustaining the survival and proliferation of Primary Effusion Lymphoma (PEL) [10], an aggressive KSHV-associated lymphoma.…”

Section: Introductionmentioning

confidence: 99%

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HSP110 Inhibition in Primary Effusion Lymphoma Cells: One Molecule, Many Pro-Survival Targets

Gonnella,

Zarrella,

Di Crosta

et al. 2023

Cancers

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Heat shock proteins (HSPs) are highly expressed in cancer cells and represent a promising target in anti-cancer therapy. In this study, we investigated for the first time the expression of high-molecular-weight HSP110, belonging to the HSP70 family of proteins, in Primary Effusion Lymphoma (PEL) and explored its role in their survival. This is a rare lymphoma associated with KSHV, for which an effective therapy remains to be discovered. The results obtained from this study suggest that targeting HSP110 could be a very promising strategy against PEL, as its silencing induced lysosomal membrane permeabilization, the cleavage of BID, caspase 8 activation, downregulated c-Myc, and strongly impaired the HR and NHEJ DNA repair pathways, leading to apoptotic cell death. Since chemical inhibitors of this HSP are not commercially available yet, this study encourages a more intense search in this direction in order to discover a new potential treatment that is effective against this and likely other B cell lymphomas that are known to overexpress HSP110.

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HSPs/STAT3 Interplay Sustains DDR and Promotes Cytokine Release by Primary Effusion Lymphoma Cells

Cited by 6 publications

References 31 publications

5-AZA Upregulates SOCS3 and PTPN6/SHP1, Inhibiting STAT3 and Potentiating the Effects of AG490 against Primary Effusion Lymphoma Cells

5-AZA Upregulates SOCS3 and PTPN6/SHP1, Inhibiting STAT3 and Potentiating the Effects of AG490 against Primary Effusion Lymphoma Cells

Conserved mechanisms of self-renewal and pluripotency in mouse and human ESCs regulated by simulated microgravity using a 3D clinostat

HSP110 Inhibition in Primary Effusion Lymphoma Cells: One Molecule, Many Pro-Survival Targets

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