Zn(II)-curc targets p53 in thyroid cancer cells

P53 mutation is a common event in many cancers, including thyroid carcinoma. Defective p53 activity promotes cancer resistance to therapies and a more malignant phenotype, acquiring oncogenic functions. Rescuing the function of mutant p53 (mutp53) protein is an attractive anticancer therapeutic strategy. Zn(II)-curc is a novel small molecule that has been shown to target mutp53 protein in several cancer cells, but its effect in thyroid cancer cells remains unclear. Here, we investigated whether Zn(II)-curc could affect p53 in thyroid cancer cells with both p53 mutation (R273H) and wild-type p53. Zn(II)-curc induced mutp53H273 downregulation and reactivation of wild-type functions, such as binding to canonical target promoters and target gene transactivation. This latter effect was similar to that induced by PRIMA-1. In addition, Zn(II)-curc triggered p53 target gene expression in wild-type p53-carrying cells. In combination treatments, Zn(II)-curc enhanced the antitumor activity of chemotherapeutic drugs, in both mutant and wild-type-carrying cancer cells. Taken together, our data indicate that Zn(II)-curc promotes the reactivation of p53 in thyroid cancer cells, providing in vitro evidence for a potential therapeutic approach in thyroid cancers

METAMORPH

Senior Project submitted to The Division of Languages and Literature of Bard College

Scattered light mapping of protoplanetary disks

High-contrast scattered light observations have revealed the surface morphology of several dozens of protoplanetary disks at optical and near-infrared wavelengths. Inclined disks offer the opportunity to measure part of the phase function of the dust grains that reside in the disk surface which is essential for our understanding of protoplanetary dust properties and the early stages of planet formation. We aim to construct a method which takes into account how the flaring shape of the scattering surface of an (optically thick) protoplanetary disk projects onto the image plane of the observer. This allows us to map physical quantities (scattering radius and scattering angle) onto scattered light images and retrieve stellar irradiation corrected (r^2-scaled) images and dust phase functions. We apply the method on archival polarized intensity images of the protoplanetary disk around HD 100546 that were obtained with VLT/SPHERE in R'-band and VLT/NACO in H- and Ks-band. The brightest side of the r^2-scaled R'-band polarized intensity image of HD 100546 changes from the far to the near side of the disk when a flaring instead of a geometrically flat disk surface is used for the r^2-scaling. The decrease in polarized surface brightness in the scattering angle range of ~40-70 deg is likely a result of the dust phase function and degree of polarization which peak in different scattering angle regimes. The derived phase functions show part of a forward scattering peak which indicates that large, aggregate dust grains dominate the scattering opacity in the disk surface. Projection effects of a protoplanetary disk surface need to be taken into account to correctly interpret scattered light images. Applying the correct scaling for the correction of stellar irradiation is crucial for the interpretation of the images and the derivation of the dust properties in the disk surface layer.Comment: Accepted for publication in A&A, 6 pages, 3 figure

Interplay between endoplasmic reticulum (ER) stress and autophagy induces mutant p53H273 degradation

The unfolded protein response (UPR) is an adaptive response to intrinsic and external stressors, and it is mainly activated by the accumulation of misfolded proteins at the endoplasmic reticulum (ER) lumen producing ER stress. The UPR signaling network is interconnected with autophagy, the proteolytic machinery specifically devoted to clearing misfolded proteins in order to survive bioenergetic stress and/or induce cell death. Oncosuppressor TP53 may undergo inactivation following missense mutations within the DNA-binding domain (DBD), and mutant p53 (mutp53) proteins may acquire a misfolded conformation, often due to the loss of the DBD-bound zinc ion, leading to accumulation of hyperstable mutp53 proteins that correlates with more aggressive tumors, resistance to therapies, and poorer outcomes. We previously showed that zinc supplementation induces mutp53 protein degradation by autophagy. Here, we show that mutp53 (i.e., Arg273) degradation following zinc supplementation is correlated with activation of ER stress and of the IRE1α/XBPI arm of the UPR. ER stress inhibition with chemical chaperone 4-phenyl butyrate (PBA) impaired mutp53 downregulation, which is similar to IRE1α/XBPI specific inhibition, reducing cancer cell death. Knockdown of mutp53 failed to induce UPR/autophagy activation indicating that the effect of zinc on mutp53 folding was likely the key event occurring in ER stress activation. Recently discovered small molecules targeting components of the UPR show promise as a novel anticancer therapeutic intervention. However, our findings showing UPR activation during mutp53 degradation indicate that caution is necessary in the design of therapies that inhibit UPR components

Shadows and cavities in protoplanetary disks: HD163296, HD141569A, and HD150193A in polarized light

The morphological evolution of dusty disks around young (few Myr-old) stars is pivotal to better understand planet formation. Since both dust grains and the global disk geometry evolve on short timescale, high-resolution imaging of a sample of objects may provide important hints towards such an evolution. We enlarge the sample of protoplanetary disks imaged in polarized light with high-resolution by observing the Herbig Ae/Be stars HD163296, HD141569A, and HD150193A. We integrate our data with previous datasets to paint a larger picture of their morphology. We report a weak detection of the disk around HD163296 in both H and Ks band. The disk is resolved as a broken ring structure with a significan surface brightness drop inward of 0.6 arcsec. No sign of extended polarized emission is detected from the disk around HD141569A and HD150193A. We propose that the absence of scattered light in the inner 0.6 arcsec around HD163296 and the non-detection of the disk around HD150193A may be due to similar geometric factors. Since these disks are known to be flat or only moderately flared, self-shadowing by the disk inner wall is the favored explanation. We show that the polarized brightness of a number of disks is indeed related to their flaring angle. Other scenarios (such as dust grain growth or interaction with icy molecules) are also discussed. On the other hand, the non-detection of HD141569A is consistent with previous datasets revealing the presence of a huge cavity in the dusty disk.Comment: 10 pages, 5 figures; accepted by Astronomy & Astrophysic

Hyperglycemia triggers HIPK2 protein degradation

Homeodomain interacting protein kinase-2 (HIPK2) is an evolutionary conserved kinase that modulates several key molecular pathways to restrain tumor growth and induce p53-depending apoptotic cell-death in response to anticancer therapies. HIPK2 silencing in cancer cells leads to chemoresistance and cancer progression, in part due to p53 inhibition. Recently, hyperglycemia has been shown to reduce p53 phosphorylation at serine 46 (Ser46), the target residue of HIPK2, thus impairing p53 apoptotic function. Here we asked whether hyperglycemia could, upstream of p53, target HIPK2. We focused on the effect of high glucose (HG) on HIPK2 protein stability and the underlying mechanisms. We found that HG reduced HIPK2 protein levels, therefore impairing HIPK2-induced p53 apoptotic activity. HG-triggered HIPK2 protein downregulation was rescued by both proteasome inhibitor MG132 and by protein phosphatase inhibitors Calyculin A (CL-A) and Okadaic Acid (OA). Looking for the phosphatase involved, we found that protein phosphatase 2A (PP2A) induced HIPK2 degradation, as evidenced by directly activating PP2A with FTY720 or by silencing PP2A with siRNA in HG condition. The effect of PP2A on HIPK2 protein degradation could be in part due to hypoxia-inducible factor-1 (HIF-1) activity which has been previously shown to induce HIPK2 proteasomal degradation through several ubiquitin ligases. Validation analysed performed with HIF-1α dominant negative or with silencing of Siah2 ubiquitin ligase clearly showed rescue of HG-induced HIPK2 degradation. These findings demonstrate how hyperglycemia, through a complex protein cascade, induced HIPK2 downregulation and consequently impaired p53 apoptotic activity, revealing a novel link between diabetes/obesity and tumor resistance to therapies

Reduced chemotherapeutic sensitivity in high glucose condition: implication of antioxidant response

Resistance to chemotherapy represents a major obstacle to successful treatment. The generation of reactive oxygen species (ROS) has been directly linked to the cytotoxic effects of several antitumor agents, including Adriamycin (ADR), and modulation of the oxidative balance has been implicated in the development and/or regulation of resistance to chemotherapeutic drugs. We recently showed that high glucose (HG) markedly diminished the cancer cell death induced by anticancer agents such as ADR. In the present study we attempted to evaluate the mechanism that impaired the cytotoxic effect of ADR in HG. We found that, in colon cancer cells, HG attenuated ADR-induced ROS production that consequently diminished ADR-induced H2AX phosphorylation and micronuclei (MN) formation. Mechanistically, HG attenuation of ADR-induced ROS production correlated with increased antioxidant response promoted by NRF2 activity. Thus, pharmacologic inhibition of NRF2 pathway by brusatol re-established the ADR cytotoxic effect impaired by HG. Together, the data provide new insights into chemotherapeutic-resistance mechanisms in HG condition dictated by increased NRF2-induced antioxidant response and how they may be overcome in order to restore chemosensitivity and ADR-induced cell death