Retraction Note: MEK inhibitors induce apoptosis via FoxO3a-dependent PUMA induction in colorectal cancer cells
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Collaborative orchestration of BH3-only proteins governs Bak/Bax-dependent hepatocyte apoptosis under antiapoptotic protein-deficiency in mice
The fine-tuned balance between anti-apoptotic Bcl-2 family proteins, such as Bcl-xL and Mcl-1, and pro-apoptotic Bcl-2 family proteins, like Bak and Bax, is crucial for maintaining hepatocyte integrity. BH3-only proteins, including Bid, Bim, Puma, Noxa, Bad, Bmf, Bik and Hrk, serve as apoptosis initiators. They are activated by various stimuli, which leads to Bak/Bax activation. We previously reported that Bid and Bim contributed to hepatocyte apoptosis through Bak/Bax activation in the absence of anti-apoptotic proteins Bcl-xL and/or Mcl-1. However, the comprehensive involvement of all eight BH3-only proteins in Bak/Bax-dependent hepatocyte apoptosis remains unclear. Puma disruption suppressed hepatocyte apoptosis in hepatocyte-specific Bcl-xL or Mcl-1 knockout (Bcl-xLΔHep/ΔHep or Mcl-1ΔHep/ΔHep) mice. Disruption of Bid and Bim partially prevented lethality in Mcl-1ΔHep/+ Bcl-xLΔHep/ΔHep mice, although severe hepatocyte apoptosis persisted, which was suppressed by additional Puma disruption. However, hepatocyte apoptosis was still induced compared to that in Mcl-1ΔHep/+ Bcl-xLΔHep/ΔHep BaxΔHep/ΔHep Bak−/− mice. Triple disruption of Bid, Bim and Puma did not prevent induction of hepatocyte apoptosis in tamoxifen-induced Mcl-1iΔHep/iΔHep Bcl-xLiΔHep/iΔHep mice. Primary hepatocytes, isolated from Mcl-1fl/fl Bcl-xLfl/fl Bid−/− Bim−/− Puma−/− mice and immortalized, underwent apoptosis with doxycycline-dependent Cre recombination. Among the remaining five BH3-only proteins, Bik and Hrk were not expressed in these cells, and Noxa knockdown, but not Bad or Bmf knockdown, reduced apoptosis. Noxa disruption alleviated hepatocyte apoptosis in Mcl-1ΔHep/ΔHep mice and tamoxifen-induced Mcl-1iΔHep/iΔHep Bcl-xLiΔHep/iΔHep Bid−/− Bim−/− Puma−/− mice, prolonging survival. Apoptosis persisted in immortalized primary hepatocytes isolated from Mcl-1fl/fl Bcl-xLfl/fl Bid−/− Bim−/− Puma−/− Noxa−/− mice where doxycycline-dependent Cre recombination was induced, but was completely suppressed by Bak/Bax knockdown, while Bad or Bmf knockdown had no effect. In conclusion, among the eight BH3-only proteins, Puma and Noxa, alongside Bid and Bim, contributed to Bak/Bax-dependent hepatocyte apoptosis, but not indispensably, in the absence of Mcl-1 and Bcl-xL.
Targeting of TAMs: can we be more clever than cancer cells?
With increasing incidence and geography, cancer is one of the leading causes of death, reduced quality of life and disability worldwide. Principal progress in the development of new anticancer therapies, in improving the efficiency of immunotherapeutic tools, and in the personification of conventional therapies needs to consider cancer-specific and patient-specific programming of innate immunity. Intratumoral TAMs and their precursors, resident macrophages and monocytes, are principal regulators of tumor progression and therapy resistance. Our review summarizes the accumulated evidence for the subpopulations of TAMs and their increasing number of biomarkers, indicating their predictive value for the clinical parameters of carcinogenesis and therapy resistance, with a focus on solid cancers of non-infectious etiology. We present the state-of-the-art knowledge about the tumor-supporting functions of TAMs at all stages of tumor progression and highlight biomarkers, recently identified by single-cell and spatial analytical methods, that discriminate between tumor-promoting and tumor-inhibiting TAMs, where both subtypes express a combination of prototype M1 and M2 genes. Our review focuses on novel mechanisms involved in the crosstalk among epigenetic, signaling, transcriptional and metabolic pathways in TAMs. Particular attention has been given to the recently identified link between cancer cell metabolism and the epigenetic programming of TAMs by histone lactylation, which can be responsible for the unlimited protumoral programming of TAMs. Finally, we explain how TAMs interfere with currently used anticancer therapeutics and summarize the most advanced data from clinical trials, which we divide into four categories: inhibition of TAM survival and differentiation, inhibition of monocyte/TAM recruitment into tumors, functional reprogramming of TAMs, and genetic enhancement of macrophages.
Enhancer reprogramming: critical roles in cancer and promising therapeutic strategies
Transcriptional dysregulation is a hallmark of cancer initiation and progression, driven by genetic and epigenetic alterations. Enhancer reprogramming has emerged as a pivotal driver of carcinogenesis, with cancer cells often relying on aberrant transcriptional programs. The advent of high-throughput sequencing technologies has provided critical insights into enhancer reprogramming events and their role in malignancy. While targeting enhancers presents a promising therapeutic strategy, significant challenges remain. These include the off-target effects of enhancer-targeting technologies, the complexity and redundancy of enhancer networks, and the dynamic nature of enhancer reprogramming, which may contribute to therapeutic resistance. This review comprehensively encapsulates the structural attributes of enhancers, delineates the mechanisms underlying their dysregulation in malignant transformation, and evaluates the therapeutic opportunities and limitations associated with targeting enhancers in cancer.
Mitochondrial priming and response to BH3 mimetics in “one-two punch” senogenic-senolytic strategies
A one-two punch sequential regimen of senescence-inducing agents followed by senolytic drugs has emerged as a novel therapeutic strategy in cancer. Unfortunately, cancer cells undergoing therapy-induced senescence (TIS) vary widely in their sensitivity to senotherapeutics, and companion diagnostics to predict the response of TIS cancer cells to a specific senolytic drug are lacking. Here, we hypothesized that the ability of the BH3 profiling assay to functionally measure the mitochondrial priming state—the proximity to the apoptotic threshold—and the dependencies on pro-survival BCL-2 family proteins can be exploited to inform the sensitivity of TIS cancer cells to BH3-mimetics. Replicative, mitotic, oxidative, and genotoxic forms of TIS were induced in p16-null/p53-proficient, BAX-deficient, and BRCA1-mutant cancer cells using mechanistically distinct TIS-inducing cancer therapeutics, including palbociclib, alisertib, doxorubicin, bleomycin, and olaparib. When the overall state of mitochondrial priming and competence was determined using activator peptides, the expected increase in overall mitochondrial priming was an exception rather than a generalizable feature across TIS phenotypes. A higher level of overall priming paralleled a higher sensitivity of competent TIS cancer cells to BCL-2/BCL-xL- and BCL-xL-targeted inhibitors when comparing TIS phenotypes among themselves. Unexpectedly, however, TIS cancer cells remained equally or even less overally primed than their proliferative counterparts. When sensitizing peptides were used to map dependencies on anti-apoptotic BCL-2 family proteins, competent TIS cancer cells appeared to share a dependency on BCL-xL. Furthermore, regardless of senescence-inducing therapeutic, stable/transient senescence acquisition, or genetic context, all TIS phenotypes shared a variable but significant senolytic response to the BCL-xL-selective BH3 mimetic A1331852. These findings may help to rethink the traditional assumption of the primed apoptotic landscape of TIS cancer cells. BCL-xL is a conserved anti-apoptotic effector of the TIS BCL2/BH3 interactome that can be exploited to maximize the efficacy of “one-two punch” senogenic-senolytic strategies.
Insights on the crosstalk among different cell death mechanisms
The phenomenon of cell death has garnered significant scientific attention in recent years, emerging as a pivotal area of research. Recently, novel modalities of cellular death and the intricate interplay between them have been unveiled, offering insights into the pathogenesis of various diseases. This comprehensive review delves into the intricate molecular mechanisms, inducers, and inhibitors of the underlying prevalent forms of cell death, including apoptosis, autophagy, ferroptosis, necroptosis, mitophagy, and pyroptosis. Moreover, it elucidates the crosstalk and interconnection among the key pathways or molecular entities associated with these pathways, thereby paving the way for the identification of novel therapeutic targets, disease management strategies, and drug repurposing.
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