Medicine and Health Sciences Commons^™

Activation Of Lxrβ Inhibits Tumor Respiration And Is Synthetically Lethal With Bcl-Xl Inhibition, Trang Thi Thu Nguyen, Chiaki Tsuge Ishida, Enyuan Shang, Chang Shu, Consuelo Torrini, Yiru Zhang, Elena Bianchetti, Maria J. Sanchez-Quintero, Giulio Kleiner, Catarina M. Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Peter Canoll, Markus D. Siegelin

Publications and Research

Liver-X-receptor (LXR) agonists are known to bear anti-tumor activity. However, their efficacy is limited and additional insights regarding the underlying mechanism are necessary. By performing transcriptome analysis coupled with global polar metabolite screening, we show that LXR agonists, LXR623 and GW3965, enhance synergistically the anti-proliferative effect of BH3 mimetics in solid tumor malignancies, which is predominantly mediated by cell death with features of apoptosis and is rescued by exogenous cholesterol. Extracellular flux analysis and carbon tracing experiments (U-¹³C-glucose and U-¹³C-glutamine) reveal that within 5 h, activation of LXRβ results in reprogramming of tumor cell metabolism, leading …

Cc Chemokine Ccl1 Receptor Ccr8 Mediates Conversion Of Mesenchymal Stem Cells To Embryoid Bodies Expressing Foxp3+Ccr8+ Regulatory T Cells, Nasreen Haque, Tuteja Akaash, Niloufar Haque

Publications and Research

Embryoid bodies (EBs) are three dimensional aggregates of pluripotent stem cells primarily used to investigate morphogenesis and cell toxicity, are also attractive tools in regenerative medicine. While embryonic stem cells (ESCs) and induced pluripotent cells (IPSCs) have been shown to form EBs in mouse, primate and humans, EB formation have not been previously demonstrated in mesenchymal stem cells (MSCs). Here we show that rat MSCs form EBs; which express regulatory T cell (Treg) marker Foxp3 and CC chemokine CCL1 receptor CCR8. We show a novel method for formation of EBs from MSCs under stress and demonstrate that the induction of …

Activation Of Lxr Receptors And Inhibition Of Trap1 Causes Synthetic Lethality In Solid Tumors, Trang Thi Thu Nguyen, Chiaki Tsuge Ishida, Enyuan Shang, Chang Shu, Elena Bianchetti, Georg Karpel-Massler, Markus D. Siegelin

Publications and Research

Cholesterol is a pivotal factor for cancer cells to entertain their relentless growth. In this case, we provide a novel strategy to inhibit tumor growth by simultaneous activation of liver-X-receptors and interference with Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1). Informed by a transcriptomic and subsequent gene set enrichment analysis, we demonstrate that inhibition of TRAP1 results in suppression of the cholesterol synthesis pathway in stem-like and established glioblastoma (GBM) cells by destabilizing the transcription factor SREBP2. Notably, TRAP1 inhibition induced cell death, which was rescued by cholesterol and mevalonate. Activation of liver X receptor (LXR) by a clinically validated …

Dietary Polyphenols, Resveratrol And Pterostilbene Exhibit Antitumor Activity On An Hpv E6-Positive Cervical Cancer Model: An In Vitro And In Vivo Analysis, Kaushiki Chatterjee, Sumit Mukherjee, Jonathan Vanmanen, Probal Banerjee, Jimmie E. Fata

Publications and Research

Human papilloma virus (HPV)-induced cervical cancer is one of themost frequent cancers in women residing in underdeveloped countries. Natural compounds like polyphenols continue to be of scientific interest as non-toxic effective alternative treatments. Our previous work showed the efficacy of two polyphenols, resveratrol, and pterostilbene on human HeLa cells. Here we explored the in vitro anti-cancer activity and in vivo anti-tumor potential of these two structurally similar compounds on HPV oncogene E6 and E7 positive murine TC1 cells. In vitro analysis confirmed the cytotoxic potential of both resveratrol and pterostilbene compounds with each having a low IC50 value and each …

Effects Of Vitamin D3 And Its Chemical Analogs On The Growth Of Hodgkin’S Lymphoma, In Vitro, Rajendra Ghardbaran, Bo Zhang, Luis Valerio, Onyekwere Onwumere, Madeline Wong, Jason Mighty, Stephen Redenti

Publications and Research

Objective: Vitamin D receptor (VDR) activities have been noted for a number of B cell malignancies which showed varying sensitivities to vitamin D3 (1,25-dihydroxyvitamin D3, VD3, calcitriol) and its synthetic analogs. The objective of this study was to address the potential effects of VD3 and vitamin D3 analogs (VDAs) on the growth of Hodgkin’s lymphoma (HL), a malignant pathology of B cell origin, in vitro.

Results: Immunofluorescence staining showed the expression of VDR by primary Hodgkin’s (H) and Reed–Sternberg (RS)—HRS-tumor cells in HL histological sections. Western blot analyses revealed expression of VDR in the HL cell lines Hs445, HDLM2, KMH2, …

Dual Complementary Liposomes Inhibit Triple-Negative Breast Tumor Progression And Metastasis, Peng Guo, Jiang Yang, Daxing Liu, Lan Huang, Gillian Fell, Jin Huang, Marsha A. Moses, Debra T. Auguste

Publications and Research

Distinguishing malignant cells from non-neoplastic ones is a major challenge in triple-negative breast cancer (TNBC) treatment. Here, we developed a complementary targeting strategy that uses precisely matched, multivalent ligand-receptor interactions to recognize and target TNBC tumors at the primary site and metastatic lesions. We screened a panel of cancer cell surface markers and identified intercellular adhesion molecule–1 (ICAM1) and epithelial growth factor receptor (EGFR) as optimal candidates for TNBC complementary targeting. We engineered a dual complementary liposome (DCL) that precisely complements the molecular ratio and organization of ICAM1 and EGFR specific to TNBC cell surfaces. Our in vitro mechanistic studies …

Microrna-4719 And Microrna-6756-5p Correlate With Castration-Resistant Prostate Cancer Progression Through Interleukin-24 Regulation, Dibash K. Das, Leah Persaud, Moira Sauane

Publications and Research

Prostate cancer (PCa) is the second leading cause of cancer death in the United States. The five-year survival rate for men diagnosed with localized PCa is nearly 100%, yet for those diagnosed with aggressive PCa, it is less than 30%. The pleiotropic cytokine Interleukin-24 (IL-24) has been shown to specifically kill PCa cells compared to normal cells when overexpressed in both in vitro and in vivo studies. Despite this, the mechanisms regulating IL-24 in PCa are not well understood. Since specific microRNAs (miRNAs) are dysregulated in PCa, we used miRNA target prediction algorithm tools to identify miR-4719 and miR-6556-5p as …