MCL1 (myeloid cell leukemia-1) is a widely recognized pro-survival member of the Bcl-2 (B-cell lymphoma protein 2) family and a promising target for cancer therapy. While the role MCL1 plays in apoptosis is well defined, its participation in emerging non-apoptotic signaling pathways is only beginning to be appreciated. Here, we synthesize studies characterizing MCL1s influence on cell proliferation, DNA damage response, autophagy, calcium handling, and mitochondrial quality control to highlight the broader scope that MCL1 plays in cellular homeostasis regulation. Throughout this review, we discuss which pathways are likely to be impacted by emerging MCL1 inhibitors, as well as highlight non-cancerous disease states that could deploy Bcl-2 homology 3 (BH3)-mimetics in the future.
MCL1, an anti-apoptotic protein that controls chemosensitivity and cell fate through its regulation of intrinsic apoptosis, has been identified as a high-impact target in anti-cancer therapeutic development. With MCL1-specific inhibitors currently in clinical trials, it is imperative that we understand the roles that MCL1 plays in cells, especially when targeting the Bcl-2 homology 3 (BH3) pocket, the central region of MCL1 that mediates apoptotic regulation. Here, we establish that MCL1 has a direct role in controlling p73 transcriptional activity, which modulates target genes associated with DNA damage response, apoptosis, and cell cycle progression. This interaction is mediated through the reverse BH3 (rBH3) motif in the p73 tetramerization domain, which restricts p73 assembly on DNA. Here, we provide a novel mechanism for protein-level regulation of p73 transcriptional activity by MCL1, while also framing a foundation for studying MCL1 inhibitors in combination with platinum-based chemotherapeutics. More broadly, this work expands the role of Bcl-2 family signaling beyond cell fate regulation.
Glioblastoma (GBM) is an aggressive malignancy with limited effectiveness of standard of care therapies including surgery, radiation, and temozolomide chemotherapy necessitating novel therapeutics. Unfortunately, GBMs also harbor several signaling alterations that protect them from traditional therapies that rely on apoptotic programmed cell death. Because almost all GBM tumors have dysregulated phosphoinositide signaling as part of that process, we hypothesized that peptide mimetics derived from the phospholipid binding domain of Myristoylated alanine-rich C-kinase substrate (MARCKS) could serve as a novel GBM therapeutic. Using molecularly classified patient-derived xenograft (PDX) lines, cultured in stem-cell conditions, we demonstrate that cell permeable MARCKS effector domain (ED) peptides potently target all GBM molecular classes while sparing normal human astrocytes. Cell death mechanistic testing revealed that these peptides produce rapid cytotoxicity in GBM that overcomes caspase inhibition. Moreover, we identify a GBM-selective cytolytic death mechanism involving plasma membrane targeting and intracellular calcium accumulation. Despite limited relative partitioning to the brain, tail vein peptide injection revealed tumor targeting in intracranially implanted GBM PDX. These results indicate that MARCKS ED peptide therapeutics may overcome traditional GBM resistance mechanisms, supporting further development of similar agents.
INTRODUCTION AND OBJECTIVE: With new options appearing in adjuvant setting, clinical biomarkers to predict recurrence after radical surgery for high-risk renal cell carcinoma (hrRCC) is in need but scarcely investigated. We aimed to verify the predictive value of perioperative C-reactive protein (CRP) kinetics on RCC recurrence.METHODS: We retrospectively evaluated 154 patients who underwent curative surgery for high-risk (!pT3 or N0-2 and M0) RCC at two institutions between 2008 and 2020. Serum CRP (mg/dL) within one months before (baseline) and within three months (post) after surgery were obtained. Patients were classified into Normal (<0.5 at baseline) and High (!0.5 at baseline) according to baseline CRP. The High group were further classified into Normalized (<0.5 at post) or non-normalized (!0.5 at post), and recurrence-free survival (RFS) was compared between groups. Factors for RFS were further analyzed using multivariable Cox hazards model. C-index for accuracy of predicting RFS was compared with and without addition or CRP kinetics to preexisting models.RESULTS: The RFS was significantly shorter in High (n[72, 46.8) compared to Normal (n[82, 53.2%) group (9.7 vs. 66.7 months, p <0.001). Within High group, non-normalized (n[27, 17.5%) patients showed significantly shorter RFS compared to Normalized (n[45, 29.2%) group (6.2 vs. 10.0, p[0.013). In the multivariable analysis both baseline CRP (HR: 2.05, p[0.003) and kinetics (HR: 2.62, p <0.001) effectively predicted RFS, with HR being higher for kinetics. Higher C-index improvement was observed with CRP kinetics than the baseline CRP levels when added to factors included in Karakiewicz and UCLA Integrated Staging System models.CONCLUSIONS: CRP kinetics effectively predict RCC recurrence after surgery, and may aid in decision-making for adjuvant systemic therapy.
nephrogenic progenitors (NPs) expressing SIX2 and CITED1 (the master regulators of renal development) present characteristics of cancer stem cells (CSCs) and are the ones driving WT. We have also studied the role of integrins in these NPs in regulating WT development.METHODS: WT and human fetal kidney (hFK) samples were histologically analyzed, digested to single-cell suspension, incubated with Smartflare-probe to isolate SIX2þCITED1þ cells, and processed for RNA-seq, single-cell RNA-seq and spatial transcriptomics. Xenografts of WT-NPs and hFK-NPs were generated and tumor formation was assessed. Analyses of mechanisms that regulate selfrenewal vs. differentiation were performed in vitro and in vivo. Knockdown with miREs against SIX2 and CITED1 was performed on WT-NPs and processed for RNA-seq.RESULTS: By comparing NPs from different WT subtypes and NPs from hFK we identified that cells expressing SIX2 and CITED1 fulfill CSC criteria, reliably recapitulating WT in transplantation studies. We showed that self-renewal vs. differentiation of SIX2þCITED1þ WT CSCs is regulated by the interplay between integrins ITGB1 and ITGB4. WT transplantation studies show that blocking ITGB1 or ITGB4 leads to higher number of SIX2þCITED1þ cells in the xenografts. Knockdown of SIX2 and CITED1 increased expression of kidney differentiation markers LHX1, WNT7B, PODXL, MECOM, reduced expression of nephrogenic markers MEOX1, TMEM100, EYA1, MAYFB, and increased expression of ITGB1, ITGB4, and LAMA5.CONCLUSIONS: These studies define SIX2þCITED1þ cells as the nephrogenic CSCs of WT, where ITGB1 and ITGB4 interplay may play a role in self-renewal vs. differentiation and serve as a potential target for new strategies to treat WT.
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