HMGB1 knockdown increases MM cell vulnerability by regulating autophagy and DNA damage repair

Guo, Xing; He, Donghua; Zhang, Enfan; Chen, Jing; Chen, Qingxiao; Li, Yang; Yang, Li; Yang, Yang; Zhao, Yi; Wang, Gang; He, Jingsong; Zhang, Cai

doi:10.1186/s13046-018-0883-3

Cited by 28 publications

(32 citation statements)

References 43 publications

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“…HMGB1 could participate in DNA damage repair and autophagy. In contrast, when HMGB1 is downregulated, the sensitivity of MM cells to dexamethasone (Dex) is enhanced by activating the mTOR pathway to inhibit autophagy and induce apoptosis [143]. Similarly, Gao et al found that the expression of the lncRNA MALAT-1 and HMGB1 was dramatically increased in patients with untreated MM, while MALAT-1 expression and HMGB1 protein levels in patients with complete remission were significantly decreased.…”

Section: Multiple Myelomamentioning

confidence: 99%

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

et al. 2020

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High mobility group box 1 (HMGB1) is a nonhistone chromatin-associated protein that has been widely reported to play a pivotal role in the pathogenesis of hematopoietic malignancies. As a representative damage-associated molecular pattern (DAMP), HMGB1 normally exists inside cells but can be secreted into the extracellular environment through passive or active release. Extracellular HMGB1 binds with several different receptors and interactors to mediate the proliferation, differentiation, mobilization, and senescence of hematopoietic stem cells (HSCs). HMGB1 is also involved in the formation of the inflammatory bone marrow (BM) microenvironment by activating proinflammatory signaling pathways. Moreover, HMGB1-dependent autophagy induces chemotherapy resistance in leukemia and multiple myeloma. In this review, we systematically summarize the emerging roles of HMGB1 in carcinogenesis, progression, prognosis, and potential clinical applications in different hematopoietic malignancies. In summary, targeting the regulation of HMGB1 activity in HSCs and the BM microenvironment is highly beneficial in the diagnosis and treatment of various hematopoietic malignancies.

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Section: Multiple Myelomamentioning

confidence: 99%

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

et al. 2020

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“…Consistent with CASP1 activation and the ballooning phenotype, a signaling cascade of HMGB1 translocation from the nucleus to the cytoplasm was observed in D089 treated myeloma cells. HMGB1 translocation is a DAMP signal for inflammasome activation [ 68 , 69 ]. D089 triggered an increase in NLRP3, ASC and ASC specks which are key components of inflammasome/ pyroptosome complex formation.…”

Section: Discussionmentioning

confidence: 99%

A Small Molecule Stabilizer of the MYC G4-Quadruplex Induces Endoplasmic Reticulum Stress, Senescence and Pyroptosis in Multiple Myeloma

Gaikwad

Phyo

Arteaga

et al. 2020

Cancers

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New approaches to target MYC include the stabilization of a guanine-rich, G-quadruplex (G4) tertiary DNA structure in the NHE III region of its promoter. Recent screening of a small molecule microarray platform identified a benzofuran, D089, that can stabilize the MYC G4 and inhibit its transcription. D089 induced both dose- and time-dependent multiple myeloma cell death mediated by endoplasmic reticulum induced stress. Unexpectedly, we uncovered two mechanisms of cell death: cellular senescence, as evidenced by increased levels of p16, p21 and γ-H2AX proteins and a caspase 3-independent mechanism consistent with pyroptosis. Cells treated with D089 exhibited high levels of the cleaved form of initiator caspase 8; but failed to show cleavage of executioner caspase 3, a classical apoptotic marker. Cotreatment with the a pan-caspase inhibitor Q-VD-OPh did not affect the cytotoxic effect of D089. In contrast, cleaved caspase 1, an inflammatory caspase downstream of caspases 8/9, was increased by D089 treatment. Cells treated with D089 in addition to either a caspase 1 inhibitor or siRNA-caspase 1 showed increased IC50 values, indicating a contribution of cleaved caspase 1 to cell death. Downstream effects of caspase 1 activation after drug treatment included increases in IL1B, gasdermin D cleavage, and HMGB1 translocation from the nucleus to the cytoplasm. Drug treated cells underwent a ‘ballooning’ morphology characteristic of pyroptosis, rather than ‘blebbing’ typically associated with apoptosis. ASC specks colocalized with NLRP3 in proximity ligation assays after drug treatment, indicating inflammasome activation and further confirming pyroptosis as a contributor to cell death. Thus, the small molecule MYC G4 stabilizer, D089, provides a new tool compound for studying pyroptosis. These studies suggest that inducing both tumor senescence and pyroptosis may have therapeutic potential for cancer treatment.

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“…High mobility group protein B1 (HMGB1) is a critical regulator of autophagy that is often upregulated in MM [112,113] . Specifically, HMGB1 binds competitively to BECLIN-1 causing BCL-2 displacement and autophagy induction [112] .…”

Section: Autophagy Inhibitors + Dna-damaging Chemotherapymentioning

confidence: 99%

“…Specifically, HMGB1 binds competitively to BECLIN-1 causing BCL-2 displacement and autophagy induction [112] . A study found that HMGB1 overexpression in MM was associated with mTOR inhibition, autophagy induction, and reduced sensitivity to dexamethasone [113] . Conversely, knockdown of HMGB1 increased apoptosis in MM cells exposed to dexamethasone [113] .…”

Section: Autophagy Inhibitors + Dna-damaging Chemotherapymentioning

confidence: 99%

“…A study found that HMGB1 overexpression in MM was associated with mTOR inhibition, autophagy induction, and reduced sensitivity to dexamethasone [113] . Conversely, knockdown of HMGB1 increased apoptosis in MM cells exposed to dexamethasone [113] . HMGB1 has also been recognized a marker of induction of immunogenic cell death (ICD).…”

Section: Autophagy Inhibitors + Dna-damaging Chemotherapymentioning

confidence: 99%

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Exploiting autophagy in multiple myeloma

Ho¹,

Patel²,

Hanley³

et al. 2019

JCMT

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Multiple myeloma (MM) is a plasma cell cancer characterized by sustained endoplasmic reticulum (ER) stress and unfolded protein response activation in the setting of high rates of immunoglobulin synthesis. Consequently, MM cells rely heavily on protein quality control pathways for survival as evidenced by the clinical efficacy of proteasome inhibitors (PI). Autophagy is an intracellular self-digestion mechanism that plays a role in the ER protein quality control process. Unsurprisingly then, basal levels of autophagy were recently found to confer a survival and drugresistance benefit to MM cells. However, excessive induction of autophagy in MM cells leads to autophagic cell death, highlighting the double-edged nature of autophagy modulation in MM. This review provides an overview of the role that autophagy plays in MM pathogenesis, survival, and drug-resistance. We highlight the potential utility of therapeutically targeting autophagy in MM, focusing on preclinical data of autophagic modulators in combination with alkylators, anthracyclines, PI, and immunomodulatory drugs.

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HMGB1 knockdown increases MM cell vulnerability by regulating autophagy and DNA damage repair

Cited by 28 publications

References 43 publications

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

A Small Molecule Stabilizer of the MYC G4-Quadruplex Induces Endoplasmic Reticulum Stress, Senescence and Pyroptosis in Multiple Myeloma

Exploiting autophagy in multiple myeloma

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