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Herein, we screened a novel inhibitor of the Hsp70-Bim protein-protein interaction (PPI), S1g-2 , from a Bcl-2 inhibitor library; this compound specifically disrupted the Hsp70-Bim PPI by direct binding to an unknown site adjacent to that of an allosteric Hsp70 inhibitor MKT-077 , showing binding affinity in sub-μM concentration range. S1g-2 exhibited overall 5–10-fold higher apoptosis-inducing activity in CML cells, primary CML blasts, and BCR-ABL-transformed BaF3 cells than other cancer cells, normal lymphocytes, and BaF3 cells, illustrating Hsp70-Bim PPI driven by BCR-ABL protects CML through oncoclient proteins that enriched in three pathways: eIF2 signaling, the regulation of eIF4E and p70S6K signaling, and the mTOR signaling pathways. Moreover, S1g-2 progressively enhanced lethality along with the increase in BCR-ABL-independent TKI resistance in the K562 cell lines and is more effective in primary samples from BCR-ABL-independent TKI-resistant patients than those from TKI-sensitive patients. By comparing the underlying mechanisms of S1g-2 , MKT-077 , and an ATP-competitive Hsp70 inhibitor VER-155008 , the Hsp70-Bim PPI was identified to be a CML-specific target to protect from TKIs through the above three oncogenic signaling pathways. The in vivo activity against CML and low toxicity endows S1g-2 a first-in-class promising drug candidate for both TKI-sensitive and resistant CML.

Parthanatos represents an alternative form of regulated cell death (RCD) mediated by poly (ADP-ribose) polymerase-1 (PARP-1). However, the underlying mechanisms and physiological significance of parthanatos are poorly understood. In this study, we investigated molecular mechanisms of parthanatos in human fibrosarcoma HT1080 cells using biochemical and cellular experiments, and found that parthanatos induced by the alkylating agent N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) is mediated by two alternative pathways that depend on pro-death Bcl-2 family proteins BAX/BAK or Bcl-2-interacting mediator of cell death (Bim). Moreover, we found that MNNG activates AMP-activated protein kinase (AMPK) through PARP-1-dependent ATP depletion, and then AMPK selectively downregulates MNNG-induced parthanatos mediated by Bim but not BAX/BAK. Under unstimulated conditions, expression levels of Bim were below the detection limit. Interestingly, MNNG strongly upregulated the protein expression levels of Bim, but only when the activation of AMPK was inhibited. These observations suggest that the AMPK signaling pathways activated by PARP-1-dependent ATP depletion limit parthanatos by blocking the Bim upregulation triggering Bim-mediated parthanatos. Thus, our results demonstrate a novel relationship between AMPK and parthanatos, which may provide insights into the physiological roles of parthanatos.

BIM is the master BH3-only BCL-2 family regulator of lymphocyte survival. To understand how long-term loss of BIM affects apoptotic resistance in T cells we studied animals with T cell-specific deletion of Bim. Unlike CD19CREBimfl/fl animals, LCKCREBimfl/fl mice have pronounced early lymphocytosis followed by normalization of lymphocyte counts over time. This normalization occurred in mature T cells, as thymocyte development and apoptotic sensitivity remained abnormal in LCKCREBimfl/fl mice. T cells from aged mice experienced normalization of their absolute cell numbers and responses against various apoptotic stimuli. mRNA expression levels of BCL-2 family proteins in CD4+ and CD8+ T cells from young and old mice revealed upregulation of several BH3-only proteins, including Puma, Noxa, and Bmf. Despite upregulation of various BH3 proteins, there were no differences in anti-apoptotic BCL-2 protein dependency in these cells. However, T cells had continued resistance to direct BIM BH3-induced mitochondrial depolarization. This study further highlights the importance of BIM in cell death maintenance in T cells and provides new insight into the dynamism underlying BH3-only regulation of T cell homeostasis versus induced cell death and suggests that CD4+ and CD8+ T cells compensate differently in response to loss of Bim.

BIM is a key apoptotic protein, participating in diverse cellular processes. Interestingly, recent studies have hypothesized that BIM is associated with the extensive neuronal cell death encountered in protein misfolding diseases, such as Alzheimer’s disease. Here, we report that the core pro-apoptotic domain of BIM, the BIM-BH3 motif, forms ubiquitous amyloid fibrils. The BIM-BH3 fibrils exhibit cytotoxicity, disrupt mitochondrial functions, and modulate the structures and dynamics of mitochondrial membrane mimics. Interestingly, a slightly longer peptide in which BIM-BH3 was flanked by four additional residues, widely employed as a model of the pro-apoptotic core domain of BIM, did not form fibrils, nor exhibited cell disruptive properties. The experimental data suggest a new mechanistic role for the BIM-BH3 domain, and demonstrate, for the first time, that an apoptotic peptide forms toxic amyloid fibrils.

Loss of cellular adhesion leads to the progression of breast cancer through acquisition of anchorage independence, also known as resistance to anoikis. Although inactivation of E-cadherin is essential for acquisition of anoikis resistance, it has remained unclear how metastatic breast cancer cells counterbalance the induction of apoptosis without E-cadherin-dependent cellular adhesion. We report here that E-cadherin inactivation in breast cancer cells induces PI3K/AKT-dependent FOXO3 inhibition and identify FOXO3 as a novel and direct transcriptional activator of the pro-apoptotic protein BMF. As a result, E-cadherin-negative breast fail to upregulate BMF upon transfer to anchorage independence, leading to anoikis resistance. Conversely, expression of BMF in E-cadherin-negative metastatic breast cancer cells is sufficient to inhibit tumour growth and dissemination in mice. In conclusion, we have identified repression of BMF as a major cue that underpins anoikis resistance and tumour dissemination in E-cadherin-deficient metastatic breast cancer.

Heat‐shock protein 70 (Hsp70) is a ubiquitous stress chaperone whose over‐expression confers treatment resistance in many cancers. Recent structural and mechanistic work has uncovered an unexpected survival circuit: the proapoptotic BH3‐only protein Bim binds a nucleotide‐sensitive groove on the Hsp70 nucleotide‐binding domain, sequestering itself from Bax/Bak while allosterically accelerating Hsp70's ATPase cycle and stabilizing oncogenic clients. This Hsp70–Bim protein–protein interaction (PPI) is enriched in tyrosine‐kinase‐inhibitor (TKI)‐resistant chronic myeloid leukemia, endocrine‐refractory breast cancer, glioblastoma, and other “chaperone‐addicted” tumors, making it a selective vulnerability rather than a housekeeping liability. Early linear and stapled BH3 peptides proved the groove is drug‐addressable but suffered from poor pharmacokinetics. A fragment‐assisted screen then delivered a phenalene‐dicarbonitrile chemotype, S1g‐2, and optimized analogs that displace Bim with sub‐micromolar potency, dismantle Hsp70–client hubs, and resensitize resistant xenografts to imatinib or tamoxifen without global proteostasis collapse. Orally bioavailable wedges thus convert a seemingly flat chaperone surface into an actionable checkpoint. This review integrates structural biology, assay technology, and medicinal chemistry to chart the rise of Hsp70–Bim inhibitors, evaluates combination strategies with BH3 mimetics, TKIs, and proteasome inhibitors, and highlights remaining challenges—cross‐isoform breadth, species‐relevant toxicology, biomarker‐guided dosing, and potential impacts on antiviral immunity. Future directions include covalent or macrocyclic wedges, degrader hybrids, and adaptive pulse‐dose regimens guided by proximity‐ligation assays. Collectively, chemical disarming of the Hsp70–Bim alliance exemplifies how precision targeting of chaperone PPIs can recalibrate apoptotic thresholds and unlock new therapeutic space in oncology. Targeting a nucleotide‐sensitive groove on Hsp70 that binds the Bim BH3 helix, we integrate structures, biophysics, and SAR from peptides, fragments, and phenalene‐dicarbonitrile “wedges.” These disrupt the Hsp70–Bim complex with sub‐µM cellular engagement and in vivo activity while sparing Hsp90/mortalin. We outline biomarkers and combination strategies for “precision proteostasis” therapeutics.

Recently, statins have been demonstrated to improve cancer-related mortality or prognosis in patients of various cancers. However, the details of the apoptosis-inducing mechanisms remain unknown. This study showed that the induction of apoptosis by statins in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of mevalonate or geranylgeranyl pyrophosphate biosynthesis. In addition, statins decreased the levels of phosphorylated extracellular signal–regulated kinase 1/2 and mammalian target of rapamycin through suppressing Ras prenylation. Furthermore, inhibition of extracellular signal–regulated kinase 1/2 and mammalian target of rapamycin by statins induced Bim expression via inhibition of Bim phosphorylation and ubiquitination and cell-cycle arrest at G1 phase via enhancement of p27 expression. Moreover, combined treatment of U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, and rapamycin, a mammalian target of rapamycin inhibitor, induced Bim and p27 expressions. The present results suggested that statins induce apoptosis by decreasing the mitochondrial transmembrane potential, increasing the activation of caspase-9 and caspase-3, enhancing Bim expression, and inducing cell-cycle arrest at G1 phase through inhibition of Ras/extracellular signal–regulated kinase and Ras/mammalian target of rapamycin pathways. Therefore, our findings support the use of statins as potential anticancer agents or concomitant drugs of adjuvant therapy.

During thymic negative selection, autoreactive thymocytes carrying T cell receptor (TCR) with overtly strong affinity to self-MHC/self-peptide are removed by Bim-dependent apoptosis, but how Bim is specifically regulated to link TCR activation and apoptosis induction is unclear. Here we identify a murine T cell-specific genomic enhancer E BAB ( Bub1 - Acoxl - Bim ) , whose deletion leads to accumulation of thymocytes expressing high affinity TCRs. Consistently, E BAB knockout mice have defective negative selection and fail to delete autoreactive thymocytes in various settings, with this defect accompanied by reduced Bim expression and apoptosis induction. By contrast, E BAB is dispensable for maintaining peripheral T cell homeostasis via Bim-dependent pathways. Our data thus implicate E BAB as an important, developmental stage-specific regulator of Bim expression and apoptosis induction to enforce thymic negative selection and suppress autoimmunity. Our study unravels a part of genomic enhancer codes that underlie complex and context-dependent gene regulation in TCR signaling. Autoreactive T cells are deleted in the thymus via thymic negative selection and Bim-mediated apoptosis. Here the authors identify a cis -acting enhancer, E BAB , that is essential for proper Bim expression and apoptosis induction, and show that E BAB deficiency specifically impairs thymic negative selection without affecting peripheral T cell homeostasis.

Investigation of the relevance between cell cycle status and the bioactivity of exogenously delivered biomacromolecules is hindered by their time-consuming cell internalization and the cytotoxicity of transfection methods. In this study, we addressed these problems by utilizing the photochemical internalization (PCI) method using a peptide/protein-photosensitizer conjugate, which enables immediate cytoplasmic internalization of the bioactive peptides/proteins in a light-dependent manner with low cytotoxicity. To identify the cell-cycle dependent apoptosis, a TatBim peptide-photosensitizer conjugate (TatBim-PS) with apoptotic activity was photo-dependently internalized into HeLa cells expressing a fluorescent ubiquitination-based cell cycle indicator (Fucci2). Upon irradiation, cytoplasmic TatBim-PS internalization exceeded 95% for all cells classified in the G 1 , S, and G 2 /M cell cycle phases with no significant differences between groups. TatBim-PS-mediated apoptosis was more efficiently triggered by photoirradiation in the G 1 /S transition than in the G 1 and S/G 2 /M phases, suggesting high sensitivity of the former phase to Bim-induced apoptosis. Thus, the cell cycle dependence of Bim peptide-induced apoptosis was successfully investigated using Fucci2 indicator and the PCI method. Since PCI-mediated cytoplasmic internalization of peptides is rapid and does not span multiple cell cycle phases, the Fucci-PCI method constitutes a promising tool for analyzing the cell cycle dependence of peptides/protein functions.

Estrogen dependence is major driver of ER + breast cancer, which is associated with PI3K mutation. PI3K inhibition (PI3Ki) can restore dependence on ER signaling for some hormone therapy-resistant ER + breast cancers, but is ineffective in others. Here we show that short-term supplementation with estrogen strongly enhanced Pik3caH1047R-induced mammary tumorigenesis in mice that resulted exclusively in ER + tumors, demonstrating the cooperation of the hormone and the oncogene in tumor development. Similar to human ER + breast cancers that are endocrine-dependent or endocrine-independent at diagnosis, tumor lines from this model retained ER expression but were sensitive or resistant to hormonal therapies. PI3Ki did not induce cell death but did cause upregulation of the pro-apoptotic gene BIM. BH3 mimetics or PI3Ki were unable to restore hormone sensitivity in several resistant mouse and human tumor lines. Importantly however, combination of PI3Ki and BH3 mimetics had a profound, BIM-dependent cytotoxic effect in PIK3CA-mutant cancer cells while sparing normal cells. We propose that addition of BH3 mimetics offers a therapeutic strategy to markedly improve the cytotoxic activity of PI3Ki in hormonal therapy-resistant and ER-independent PIK3CA-mutant breast cancer.