Statins in Cancer Prevention and Therapy

Statins, a class of HMG-CoA reductase inhibitors best known for their cholesterol-reducing and cardiovascular protective activity, have also demonstrated promise in cancer prevention and treatment. This review focuses on their potential applications in head and neck cancer (HNC), a common malignancy for which established treatment often fails despite incurring debilitating adverse effects. Preclinical and clinical studies have suggested that statins may enhance HNC sensitivity to radiation and other conventional therapies while protecting normal tissue, but the underlying mechanisms remain poorly defined, likely involving both cholesterol-dependent and -independent effects on diverse cancer-related pathways. This review brings together recent discoveries concerning the anticancer activity of statins relevant to HNC, highlighting their anti-inflammatory activity and impacts on DNA-damage response. We also explore molecular targets and mechanisms and discuss the potential to integrate statins into conventional HNC treatment regimens to improve patient outcomes

Yeast cell death during DNA damage arrest is independent of caspase or reactive oxygen species

CDC13 encodes a telomere-binding protein that prevents degradation of telomeres. cdc13-1 yeast grown at the nonpermissive temperature undergo G2/M arrest, progressive chromosome instability, and subsequent cell death. Recently, it has been suggested that cell death in the cdc13-1 mutant is an active process characterized by phenotypic hallmarks of apoptosis and caspase activation. In this work, we show that cell death triggered by cdc13-1 is independent of the yeast metacaspase Yca1p and reactive oxygen species but related to cell cycle arrest per se. Inactivating YCA1 or depleting reactive oxygen species does not increase viability of cdc13-1 cells. In turn, caspase activation does not precede cell death in the cdc13-1 mutant. Yca1p activity assayed by cell binding of mammalian caspase inhibitors is confounded by artifactual labeling of dead yeast cells, which nonspecifically bind fluorochromes. We speculate that during a prolonged cell cycle arrest, cdc13-1 cells reach a critical size and die by cell lysis

Therapy-Induced Cellular Senescence: Potentiating Tumor Elimination or Driving Cancer Resistance and Recurrence?

Cellular senescence has been increasingly recognized as a hallmark of cancer, reflecting its association with aging and inflammation, its role as a response to deregulated proliferation and oncogenic stress, and its induction by cancer therapies. While therapy-induced senescence (TIS) has been linked to resistance, recurrence, metastasis, and normal tissue toxicity, TIS also has the potential to enhance therapy response and stimulate anti-tumor immunity. In this review, we examine the Jekyll and Hyde nature of senescent cells (SnCs), focusing on how their persistence while expressing the senescence-associated secretory phenotype (SASP) modulates the tumor microenvironment through autocrine and paracrine mechanisms. Through the SASP, SnCs can mediate both resistance and response to cancer therapies. To fulfill the unmet potential of cancer immunotherapy, we consider how SnCs may influence tumor inflammation and serve as an antigen source to potentiate anti-tumor immune response. This new perspective suggests treatment approaches based on TIS to enhance immune checkpoint blockade. Finally, we describe strategies for mitigating the detrimental effects of senescence, such as modulating the SASP or targeting SnC persistence, which may enhance the overall benefits of cancer treatment

Activity Assay of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Triple-Negative Breast Cancer Cells Using Peptide-Conjugated Magnetic Beads

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with limited treatment options. Epidermal growth factor receptor I (EGFR) has emerged as a promising target in TNBC. Limited success of the EGFR kinase inhibiting small molecules in clinical trials may be attributed in part to inaccuracy in identifying EGFR signatures in patient tumors. In light of the absence of a simple correlation between EGFR expression and its degree of activation, a simple and reliable tool that can quantify EGFR kinase activity in tumor samples may be of therapeutic value in predicting patient-specific EGFR targeted therapies. This study reports the development of an assay that can quantitatively profile EGFR kinase activities and inhibitor sensitivities in TNBC cell lysates by using peptide reporters covalently tethered to magnetic beads in a controlled orientation. The use of magnetic beads provides rapid sample handling and easy product isolation. The potential of this approach was demonstrated by screening a set of five clinically relevant EGFR tyrosine kinase inhibitors. Formatted for microwell plates, this magnetic bead-based kinase assay may be used as a complementary approach for direct high-throughput screening of small molecule inhibitors.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140099/1/adt.2012.454.pd

CDK-dependent Hsp70 phosphorylation controls G1 cyclin abundance and cell-cycle progression

In budding yeast, the essential functions of Hsp70 chaperones Ssa1-4 are regulated through expression level, isoform specificity, and cochaperone activity. Suggesting a novel regulatory paradigm, we find that phosphorylation of Ssa1 T36 within a cyclin-dependent kinase (CDK) consensus site conserved among Hsp70 proteins alters cochaperone and client interactions. T36 phosphorylation triggers displacement of Ydj1, allowing Ssa1 to bind the G1 cyclin Cln3 and promote its degradation. The stress CDK Pho85 phosphorylates T36 upon nitrogen starvation or pheromone stimulation, destabilizing Cln3 to delay onset of S phase. In turn, the mitotic CDK Cdk1 phosphorylates T36 to block Cln3 accumulation in G2/M. Suggesting broad conservation from yeast to human, CDK-dependent phosphorylation of Hsc70 T38 similarly regulates Cyclin D1 binding and stability. These results establish an active role for Hsp70 chaperones as signal transducers mediating growth control of G1 cyclin abundance and activity

CDK-Dependent Hsp70 Phosphorylation Controls G1 Cyclin Abundance and Cell-Cycle Progression

In budding yeast, the essential functions of Hsp70 chaperones Ssa1–4 are regulated through expression level, isoform specificity, and cochaperone activity. Suggesting a novel regulatory paradigm, we find that phosphorylation of Ssa1 T36 within a cyclin-dependent kinase (CDK) consensus site conserved among Hsp70 proteins alters cochaperone and client interactions. T36 phosphorylation triggers displacement of Ydj1, allowing Ssa1 to bind the G1 cyclin Cln3 and promote its degradation. The stress CDK Pho85 phosphorylates T36 upon nitrogen starvation or pheromone stimulation, destabilizing Cln3 to delay onset of S phase. In turn, the mitotic CDK Cdk1 phosphorylates T36 to block Cln3 accumulation in G2/M. Suggesting broad conservation from yeast to human, CDK-dependent phosphorylation of Hsc70 T38 similarly regulates Cyclin D1 binding and stability. These results establish an active role for Hsp70 chaperones as signal transducers mediating growth control of G1 cyclin abundance and activity

Dynamic Critical Behavior of an Extended Reptation Dynamics for Self-Avoiding Walks

We consider lattice self-avoiding walks and discuss the dynamic critical behavior of two dynamics that use local and bilocal moves and generalize the usual reptation dynamics. We determine the integrated and exponential autocorrelation times for several observables, perform a dynamic finite-size scaling study of the autocorrelation functions, and compute the associated dynamic critical exponents $z$. For the variables that describe the size of the walks, in the absence of interactions we find $z \approx 2.2$ in two dimensions and $z\approx 2.1$ in three dimensions. At the $\theta$-point in two dimensions we have $z\approx 2.3$.Comment: laTeX2e, 32 pages, 11 eps figure

UV-Optical Pixel Maps of Face-On Spiral Galaxies -- Clues for Dynamics and Star Formation Histories

UV and optical images of the face-on spiral galaxies NGC 6753 and NGC 6782 reveal regions of strong on-going star formation that are associated with structures traced by the old stellar populations. We make NUV--(NUV-I) pixel color-magnitude diagrams (pCMDs) that reveal plumes of pixels with strongly varying NUV surface brightness and nearly constant I surface brightness. The plumes correspond to sharply bounded radial ranges, with (NUV-I) at a given NUV surface brightness being bluer at larger radii. The plumes are parallel to the reddening vector and simple model mixtures of young and old populations, thus neither reddening nor the fraction of the young population can produce the observed separation between the plumes. The images, radial surface-brightness, and color plots indicate that the separate plumes are caused by sharp declines in the surface densities of the old populations at radii corresponding to disk resonances. The maximum surface brightness of the NUV light remains nearly constant with radius, while the maximum I surface brightness declines sharply with radius. An MUV image of NGC 6782 shows emission from the nuclear ring. The distribution of points in an (MUV-NUV) vs. (NUV-I) pixel color-color diagram is broadly consistent with the simple mixture model, but shows a residual trend that the bluest pixels in (MUV-NUV) are the reddest pixels in (NUV-I). This may be due to a combination of red continuum from late-type supergiants and [SIII] emission lines associated with HII regions in active star-forming regions. We have shown that pixel mapping is a powerful tool for studying the distribution and strength of on-going star formation in galaxies. Deep, multi-color imaging can extend this to studies of extinction, and the ages and metallicities of composite stellar populations in nearby galaxies.Comment: LaTeX with AASTeX style file, 29 pages with 12 figures (some color, some multi-part). Accepted for publication in The Astrophysical Journa