Apoptosis is a form of programmed cell death that plays a critical role in cellular homeostasis and development, including in the ovarian reserve. In humans, hundreds of thousands of oocytes are ...produced in the fetal ovary. However, the majority die by apoptosis before birth. After puberty, primordial follicles develop into mature follicles. While only a large dominant follicle is selected to ovulate, smaller ones undergo apoptosis. Despite numerous studies, the mechanism of oocyte death at the molecular level remains elusive. Over the last two and a half decades, many knockout mouse models disrupting key genes in the apoptosis pathway have been generated. In this review, we highlight some of the phenotypes and discuss distinct and overlapping roles of the apoptosis regulators in oocyte death and survival. We also review how the transcription factor p63 and its family members may trigger oocyte apoptosis in response to DNA damage.
The tumor suppressor p53 and its homologues, p63 and p73, play a pivotal role in the regulation of the DNA damage response, cellular homeostasis, development, aging, and metabolism. A number of mouse ...studies have shown that a genetic defect in the p53 family could lead to spontaneous tumor development, embryonic lethality, or severe tissue abnormality, indicating that the activity of the p53 family must be tightly regulated to maintain normal cellular functions. While the p53 family members are regulated at the level of gene expression as well as post-translational modification, they are also controlled at the level of protein stability through the ubiquitin proteasomal pathway. Over the last 20 years, many ubiquitin E3 ligases have been discovered that directly promote protein degradation of p53, p63, and p73 in vitro and in vivo. Here, we provide an overview of such E3 ligases and discuss their roles and functions.
The tumor suppressor p53, encoded by the TP53 gene, is mutated or nullified in nearly 50% of human cancers. It has long been debated whether TP53 mutations can be utilized as a biomarker to predict ...clinical outcomes of cancer patients. In this study, we applied computational methods to calculate p53 deficiency scores (PDSs) that reflect the inactivation of the p53 pathway, instead of TP53 mutation status. Compared to TP53 mutation status, the p53 deficiency gene signature is a powerful predictor of overall survival and drug sensitivity in a variety of cancer types and treatments. Interestingly, the PDSs predicted clinical outcomes more accurately than drug sensitivity in cell lines, suggesting that tumor heterogeneity and/or tumor microenvironment may play an important role in predicting clinical outcomes using p53 deficiency gene signatures.
Although it is established that fatty acid (FA) synthesis supports anabolic growth in cancer, the role of exogenous FA uptake remains elusive. Here we show that, during acquisition of resistance to ...HER2 inhibition, metabolic rewiring of breast cancer cells favors reliance on exogenous FA uptake over de novo FA synthesis. Through cDNA microarray analysis, we identify the FA transporter CD36 as a critical gene upregulated in cells with acquired resistance to the HER2 inhibitor lapatinib. Accordingly, resistant cells exhibit increased exogenous FA uptake and metabolic plasticity. Genetic or pharmacological inhibition of CD36 suppresses the growth of lapatinib-resistant but not lapatinib-sensitive cells in vitro and in vivo. Deletion of Cd36 in mammary tissues of MMTV-neu mice significantly attenuates tumorigenesis. In breast cancer patients, CD36 expression increases following anti-HER2 therapy, which correlates with a poor prognosis. Our results define CD36-mediated metabolic rewiring as an essential survival mechanism in HER2-positive breast cancer.
Display omitted
•Lapatinib-resistant breast cancer cells upregulate CD36 expression for survival•Targeting CD36 re-sensitizes lapatinib-resistant cells to HER2-inhibition•Deletion of Cd36 significantly attenuates MMTV-neu-driven mammary tumor growth•CD36 is induced by HER2-targeted therapy and predicts poor clinical prognosis
The functional significance of lipid metabolism in cancer cells is not fully understood. Feng et al. show that the fatty acid transporter CD36 is essential for survival of breast cancer cells during anti-HER2 therapy, highlighting the role of lipid metabolism in acquired resistance to targeted therapy.
Potassium loss and persistent shrinkage have both been implicated in apoptosis but their relationship and respective roles remain controversial. We approached this problem by clamping intracellular ...sodium and potassium in HeLa or MDCK cells using a combination of ionophores. Although ionophore treatment caused significant cell swelling, the initial volume could be restored and further reduced by application of sucrose. The swollen cells treated with ionophores remained viable for at least 8 h without any signs of apoptosis. Application of sucrose and the resulting shrinkage caused volume-dependent intrinsic apoptosis with all its classical features: inversion of phosphatidylserine, caspase activation and Bcl-2-dependent release of cytochrome
from mitochondria. In other experiments, apoptosis was induced by addition of the protein kinase inhibitor staurosporine at various degrees of swelling. Our results show that: (1) persistent shrinkage can cause apoptosis regardless of intracellular sodium or potassium composition or of the state of actin cytoskeleton; (2) strong potassium dependence of caspase activation is only observed in swollen cells with a reduced density of cytosolic proteins. We conclude that macromolecular crowding can be an important factor in determining the transition of cells to apoptosis.
High density of intracellular macromolecules creates a special condition known as macromolecular crowding (MC). One well-established consequence of MC is that only a slight change in the ...concentration of macromolecules (e.g., proteins) results in a shift of chemical equilibria towards the formation of macromolecular complexes and oligomers. This suggests a physiological mechanism of converting cell density changes into cellular responses. In this review, we start by providing a general overview of MC; then we examine the available experimental evidence that MC may act as a direct signaling factor in several types of cellular activities: mechano- and osmosensing, cell volume recovery in anisosmotic solutions, and apoptotic shrinkage. The latter phenomenon is analyzed in particular detail, as persistent shrinkage is known both to cause apoptosis and to occur during apoptosis resulting from other stimuli. We point to specific apoptotic reactions that involve formation of macromolecular complexes and, therefore, may provide a link between shrinkage and downstream responses.
Evading apoptosis in cancer Fernald, Kaleigh; Kurokawa, Manabu
Trends in cell biology,
12/2013, Letnik:
23, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Highlights • Cancer cells employ multiple strategies to block apoptosis. • Cancer cells modulate apoptotic signals at genomic and protein levels. • Agents that can globally alter cancer's apoptotic ...resistance may be more valuable.
Cluster of differentiation 36 (CD36) is a cell surface scavenger receptor that plays critical roles in many different types of cancer, notably breast, brain, and ovarian cancers. While it is arguably ...most well-known for its fatty acid uptake functions, it is also involved in regulating cellular adhesion, immune response, and apoptosis depending on the cellular and environmental contexts. Here, we discuss the multifaceted role of CD36 in cancer biology, such as its role in mediating metastasis, drug resistance, and immune evasion to showcase its potential as a therapeutic target. We will also review existing approaches to targeting CD36 in pre-clinical studies, as well as discuss the only CD36-targeting drug to advance to late-stage clinical trials, VT1021. Given the roles of CD36 in the etiology of metabolic disorders, such as atherosclerosis, diabetes, and non-alcoholic fatty liver disease, the clinical implications of CD36-targeted therapy are wide-reaching, even beyond cancer.
The complex process of apoptosis is orchestrated by caspases, a family of cysteine proteases with unique substrate specificities. Accumulating evidence suggests that cell death pathways are finely ...tuned by multiple signaling events, including direct phosphorylation of caspases, whereas kinases are often substrates of active caspases. Importantly, caspase-mediated cleavage of kinases can terminate prosurvival signaling or generate proapoptotic peptide fragments that help to execute the death program and facilitate packaging of the dying cells. Here, we review caspases as kinase substrates and kinases as caspase substrates and discuss how the balance between cell survival and cell death can be shifted through crosstalk between these two enzyme families.