Cancer Biology Commons^™

Desmoglein-2 As A Cancer Modulator: Friend Or Foe?, Kay Myo Min, Charlie Ffrench, Barbara Mcclure, Michael Ortiz, Emma Dorward, Michael Samuel, Lisa Ebert, Mỹ Mahoney, Claudine Bonder

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Desmoglein-2 (DSG2) is a calcium-binding single pass transmembrane glycoprotein and a member of the large cadherin family. Until recently, DSG2 was thought to only function as a cell adhesion protein embedded within desmosome junctions designed to enable cells to better tolerate mechanical stress. However, additional roles for DSG2 outside of desmosomes are continuing to emerge, particularly in cancer. Herein, we review the current literature on DSG2 in cancer and detail its impact on biological functions such as cell adhesion, proliferation, migration, invasion, intracellular signaling, extracellular vesicle release and vasculogenic mimicry. An increased understanding of the diverse repertoire of the biological …

27-Hydroxycholesterol And Dna Damage Repair: Implication In Prostate Cancer, Gloria Cecilia Galvan, Nadine Friedrich, Sanjay Das, James Daniels, Sara Pollan, Shweta Dambal, Ryusuke Suzuki, Sergio Sanders, Sungyong You, Hisashi Tanaka, Yeon-Joo Lee, Wei Yuan, Johann De Bono, Irina Vasilevskaya, Karen Knudsen, Michael Freeman, Stephen Freedland

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

INTRODUCTION: We previously reported that cholesterol homeostasis in prostate cancer (PC) is regulated by 27-hydroxycholesterol (27HC) and that CYP27A1, the enzyme that converts cholesterol to 27HC, is frequently lost in PCs. We observed that restoring the CYP27A1/27HC axis inhibited PC growth. In this study, we investigated the mechanism of 27HC-mediated anti-PC effects.

METHODS: We employed in vitro models and human transcriptomics data to investigate 27HC mechanism of action in PC. LNCaP (AR+) and DU145 (AR-) cells were treated with 27HC or vehicle. Transcriptome profiling was performed using the Affymetrix GeneChip™ microarray system. Differential expression was determined, and gene set enrichment …

Needle Biopsy Accelerates Pro-Metastatic Changes And Systemic Dissemination In Breast Cancer: Implications For Mortality By Surgery Delay, Hiroyasu Kameyama, Priya Dondapati, Reese Simmons, Macall Leslie, John Langenheim, Yunguang Sun, Misung Yi, Aubrey Rottschaefer, Rashmi Pathak, Shreya Nuguri, Kar-Ming Fung, Shirng-Wern Tsaih, Inna Chervoneva, Hallgeir Rui, Takemi Tanaka

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

ncreased breast cancer (BC) mortality risk posed by delayed surgical resection of tumor after diagnosis is a growing concern, yet the underlying mechanisms remain unknown. Our cohort analyses of early-stage BC patients reveal the emergence of a significantly rising mortality risk when the biopsy-to-surgery interval was extended beyond 53 days. Additionally, histology of post-biopsy tumors shows prolonged retention of a metastasis-permissive wound stroma dominated by M2-like macrophages capable of promoting cancer cell epithelial-to-mesenchymal transition and angiogenesis. We show that needle biopsy promotes systemic dissemination of cancer cells through a mechanism of sustained activation of the COX-2/PGE₂/EP2 feedforward loop, …

Phi-1, An Endogenous Inhibitor Protein For Protein Phosphatase-1 And A Pan-Cancer Marker, Regulates Raf-1 Proteostasis, Jason Kirkbride, Garbo Nilsson, Jee In Kim, Kosuke Takeya, Yoshinori Tanaka, Hiroshi Tokumitsu, Futoshi Suizu, Masumi Eto

Kimmel Cancer Center Faculty Papers

Raf-1, a multifunctional kinase, regulates various cellular processes, including cell proliferation, apoptosis, and migration, by phosphorylating MAPK/ERK kinase and interacting with specific kinases. Cellular Raf-1 activity is intricately regulated through pathways involving the binding of regulatory proteins, direct phosphorylation, and the ubiquitin-proteasome axis. In this study, we demonstrate that PHI-1, an endogenous inhibitor of protein phosphatase-1 (PP1), plays a pivotal role in modulating Raf-1 proteostasis within cells. Knocking down endogenous PHI-1 in HEK293 cells using siRNA resulted in increased cell proliferation and reduced apoptosis. This heightened cell proliferation was accompanied by a 15-fold increase in ERK1/2 phosphorylation. Importantly, the observed …

Kinome Profiling Identifies Mark3 And Stk10 As Potential Therapeutic Targets In Uveal Melanoma, Usman Baqai, Alison M. Kurimchak, Isabella Trachtenberg, Timothy J. Purwin, Jelan I. Haj, Anna Han, Kristine Luo, Nikole Fandino Pachon, Angela Jeon, Vivian Chua, Michael A. Davies, J Silvio Gutkind, Jeffrey L. Benovic, James S. Duncan, Andrew E. Aplin

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Most uveal melanoma cases harbor activating mutations in either GNAQ or GNA11. Despite activation of the mitogen-activated protein kinase (MAPK) signaling pathway downstream of Gαq/11, there are no effective targeted kinase therapies for metastatic uveal melanoma. The human genome encodes numerous understudied kinases, also called the "dark kinome". Identifying additional kinases regulated by Gαq/11 may uncover novel therapeutic targets for uveal melanoma. In this study, we treated GNAQ-mutant uveal melanoma cell lines with a Gαq/11 inhibitor, YM-254890, and conducted a kinase signaling proteomic screen using multiplexed-kinase inhibitors followed by mass spectrometry. We observed downregulated expression and/or activity of 22 kinases. …

Enteroendocrine Cell Regulation Of The Gut-Brain Axis, Joshua Barton, Annie Londregan, Tyler Alexander, Ariana Entezari, Manuel Covarrubias, Scott Waldman

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Enteroendocrine cells (EECs) are an essential interface between the gut and brain that communicate signals about nutrients, pain, and even information from our microbiome. EECs are hormone-producing cells expressed throughout the gastrointestinal epithelium and have been leveraged by pharmaceuticals like semaglutide (Ozempic, Wegovy), terzepatide (Mounjaro), and retatrutide (Phase 2) for diabetes and weight control, and linaclotide (Linzess) to treat irritable bowel syndrome (IBS) and visceral pain. This review focuses on role of intestinal EECs to communicate signals from the gut lumen to the brain. Canonically, EECs communicate information about the intestinal environment through a variety of hormones, dividing EECs into …

Tak1 And Tbk1 Are Differentially Required By Gmp- And Lmpp-Like Leukemia Stem Cells, Austin P. Runde, Joseph Michael Cannova, Ryan Mack, Kanak Joshi, Mark Sellin, Allan Youmaran, Mattias Lenz, Rohit Thalla, Wei Wei, Peter Breslin S.J., Jiwang Zhang

School of Medicine

Acute myeloid leukemia (AML) encompasses a diverse group of cancers that originate in the blood-forming tissues of the bone marrow. Aside from the M3 subtype (PML-RARA⁺), AML carries a 5-year survival rate of 28% for patients 20+ years of age. AML is the most common cancer of the hematopoietic system and is slightly more common in biological males; the average age at diagnosis is 68 years. Standard frontline treatment for AML is a 2-phase regimen of intensive chemotherapy (CTx) employing daunorubicin and cytarabine. Despite 60-70% of patients achieving complete remission (CR), at least half of CR-achieving patients …

Targeting Breast Cancer: The Familiar, The Emerging, And The Uncharted Territories, Hamidreza Montazeri Aliabadi, Arthur Manda, Riya Sidgal, Co Chung

Pharmacy Faculty Articles and Research

Breast cancer became the most diagnosed cancer in the world in 2020. Chemotherapy is still the leading clinical strategy in breast cancer treatment, followed by hormone therapy (mostly used in hormone receptor-positive types). However, with our ever-expanding knowledge of signaling pathways in cancer biology, new molecular targets are identified for potential novel molecularly targeted drugs in breast cancer treatment. While this has resulted in the approval of a few molecularly targeted drugs by the FDA (including drugs targeting immune checkpoints), a wide array of signaling pathways seem to be still underexplored. Also, while combinatorial treatments have become common practice in …

Α7 Nicotinic Acetylcholine Receptor Interaction With G Proteins In Breast Cancer Cell Proliferation, Motility, And Calcium Signaling, Murat Oz, Justin R. King, Keun-Hang Susan Yang, Sarah Khushaish, Yulia Tchugunova, Maitham A. Khajah, Yunus A. Luqmani, Nadine Kabbani

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Chronic smoking is a primary risk factor for breast cancer due to the presence of various toxins and carcinogens within tobacco products. Nicotine is the primary addictive component of tobacco products and has been shown to promote breast cancer cell proliferation and metastases. Nicotine activates nicotinic acetylcholine receptors (nAChRs) that are expressed in cancer cell lines. Here, we examine the role of the α7 nAChR in coupling to heterotrimeric G proteins within breast cancer MCF-7 cells. Pharmacological activation of the α7 nAChR using choline or nicotine was found to increase proliferation, motility, and calcium signaling in MCF-7 cells. This effect …

Preclinical Evaluation Of Anti-Cd38 Therapy In Mature T-Cell Neoplasms, Colleen Isabelle, William Johnson, Kathleen Mcconnell, Ashley Vogel, Jonathan Brammer, Amy Boles, Robyn Keller, Paola Sindaco, Liam Nisenfeld, Guldeep Uppal, Neda Nikbakht, Bruno Calabretta, Patrizia Porazzi, Jerald Gong, Nitin Chakravarti, Pierluigi Porcu, Anjali Mishra

Kimmel Cancer Center Faculty Papers

No abstract provided.

Enhancement Of Tki Sensitivity In Lung Adenocarcinoma Through M6a-Dependent Translational Repression Of Wnt Signaling By Circ-Fbxw7, Kai Li, Zi-Yang Peng, Rui Wang, Xiang Li, Ning Du, Da-Peng Liu, Jia Zhang, Yun-Feng Zhang, Lei Ma, Ye Sun, Shou-Ching Tang, Hong Ren, Yi-Ping Yang, Xin Sun

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Tyrosine kinase inhibitors (TKIs) that specifically target mutational points in the EGFR gene have significantly reduced suffering and provided greater relief to patients with lung adenocarcinoma (LUAD). The third-generation EGFR-TKI, Osimertinib, has been successfully employed in clinical treatments to overcome resistance to both original and acquired T790M and L858R mutational points. Nevertheless, the issue of treatment failure response has emerged as an insurmountable problem.

METHODS: By employing a combination of multiple and integrated approaches, we successfully identified a distinct population within the tumor group that plays a significant role in carcinogenesis, resistance, and recurrence. Our research suggests that addressing …

Parabens Promote Protumorigenic Effects In Luminal Breast Cancer Cell Lines With Diverse Genetic Ancestry, Jazma L. Tapia, Jillian C. Mcdonough, Emily L. Cauble, Cesar G. Gonzalez, Dede K. Teteh, Lindsey S. Treviño

Health Sciences and Kinesiology Faculty Articles

Context

One in 8 women will develop breast cancer in their lifetime. Yet, the burden of disease is greater in Black women. Black women have a 40% higher mortality rate than White women, and a higher incidence of breast cancer at age 40 and younger. While the underlying cause of this disparity is multifactorial, exposure to endocrine disrupting chemicals (EDCs) in hair and other personal care products has been associated with an increased risk of breast cancer. Parabens are known EDCs that are commonly used as preservatives in hair and other personal care products, and Black women are disproportionately exposed …

Design, Synthesis, And Antiproliferative Activity Of Benzopyran-4-One-Isoxazole Hybrid Compounds, Shilpi Gupta, Shang Eun Park, Saghar Mozaffari, Bishoy El-Aarag, Keykavous Parang, Rakesh Kumar Tiwari

Pharmacy Faculty Articles and Research

The biological significance of benzopyran-4-ones as cytotoxic agents against multi-drug resistant cancer cell lines and isoxazoles as anti-inflammatory agents in cellular assays prompted us to design and synthesize their hybrid compounds and explore their antiproliferative activity against a panel of six cancer cell lines and two normal cell lines. Compounds 5a–d displayed significant antiproliferative activities against all the cancer cell lines tested, and IC₅₀ values were in the range of 5.2–22.2 μM against MDA-MB-231 cancer cells, while they were minimally cytotoxic to the HEK-293 and LLC-PK1 normal cell lines. The IC₅₀ values of 5a–d …

Zinc Treatment Reverses And Anti-Zn-Regulated Mirs Suppress Esophageal Carcinomas In Vivo, Louise Fong, Kay Huebner, Ruiyan Jing, Karl Smalley, Christopher R Brydges, Oliver Fiehn, John Farber, Carlo M Croce

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Esophageal squamous cell carcinoma (ESCC) is a deadly disease with few prevention or treatment options. ESCC development in humans and rodents is associated with Zn deficiency (ZD), inflammation, and overexpression of oncogenic microRNAs: miR-31 and miR-21. In a ZD-promoted ESCC rat model with upregulation of these miRs, systemic antimiR-31 suppresses the miR-31-EGLN3/STK40-NF-κB-controlled inflammatory pathway and ESCC. In this model, systemic delivery of Zn-regulated antimiR-31, followed by antimiR-21, restored expression of tumor-suppressor proteins targeted by these specific miRs: STK40/EGLN3 (miR-31), PDCD4 (miR-21), suppressing inflammation, promoting apoptosis, and inhibiting ESCC development. Moreover, ESCC-bearing Zn-deficient (ZD) rats receiving Zn medication showed a 47% …

Parkin Ubiquitination Of Kindlin-2 Enables Mitochondria-Associated Metastasis Suppression, Minjeong Yeon, Irene Bertolini, Ekta Agarwal, Jagadish C Ghosh, Hsin-Yao Tang, David W. Speicher, Frederick Keeney, Khalid Sossey-Alaoui, Elzbieta Pluskota, Katarzyna Bialkowska, Edward F. Plow, Lucia R. Languino, Emmanuel Skordalakes, M Cecilia Caino, Dario C. Altieri

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Mitochondria are signaling organelles implicated in cancer, but the mechanisms are elusive. Here, we show that Parkin, an E3 ubiquitination (Ub) ligase altered in Parkinson's disease, forms a complex with the regulator of cell motility, Kindlin-2 (K2), at mitochondria of tumor cells. In turn, Parkin ubiquitinates Lys581 and Lys582 using Lys48 linkages, resulting in proteasomal degradation of K2 and shortened half-life from ∼5 h to ∼1.5 h. Loss of K2 inhibits focal adhesion turnover and β1 integrin activation, impairs membrane lamellipodia size and frequency, and inhibits mitochondrial dynamics, altogether suppressing tumor cell-extracellular matrix interactions, migration, and invasion. Conversely, Parkin does …

Oncolytic Virus Immunotherapy: Development And Potential For Cancer Treatment, Olivia Guinness

Honors Scholar Theses

The American Cancer Society estimates that in 2023, 1,958,310 new cancer cases and 609,820 cancer deaths will occur in the United States [16]. A promising therapeutic option that has been supported by recent clinical trials is the use of oncolytic viruses to treat malignant tumors. The mechanism of action of existing treatments, such as chemotherapy, radiotherapy, and surgery, differs from that of oncolytic virus therapy because oncolytic viruses are able to affect cancer cells with specificity, minimizing side effects. When infecting a normal, non-cancerous cell, oncolytic viruses do not replicate, leaving healthy cells unaffected. In tumor cells, oncolytic viruses will …

A Dna-Peptide Crosslink (Dpc) Increases Mutagenicity In Sos-Induced Escherichia Coli, Alessandra Bassani

Honors Scholar Theses

Bacteria, such as Escherichia coli, have an inducible system in response to DNA damage termed the SOS response. This system is activated when the replicative DNA polymerase (Pol) III encounters a lesion, uncouples from DNA helicase, and single-stranded DNA (ssDNA) accumulates at the replication fork. In this study, we investigated DNA-peptide crosslink (DpC), a common lesion that results from cross-linking of proteins or peptides, UV irradiation, and alkylating agents. To increase survival following formation of a lesion, the SOS response can utilize homologous recombination, translesion synthesis (TLS), or excision repair. With TLS, the levels of DNA Pol II, IV, …

Split And Join: An Efficient Approach For Simulating Stapled Intestinal Anastomosis In Virtual Reality, Di Qi, Suvranu De

Engineering Faculty Articles and Research

Colorectal cancer is a life-threatening disease. It is the second leading cause of cancer-related deaths in the United States. Stapled anastomosis is a rapid treatment for colorectal cancer and other intestinal diseases and has become an integral part of routine surgical practice. However, to the best of our knowledge, there is no existing work simulating intestinal anastomosis that often involves sophisticated soft tissue manipulations such as cutting and stitching. In this paper, for the first time, we propose a novel split and join approach to simulate a side-to-side stapled intestinal anastomosis in virtual reality. We mimic the intestine model using …

Gene Expression Under Combined Hypoxia And Acidosis In Chondrosarcoma, Michael Stacey, Kostika Vangjeli, Christopher Osgood

Bioelectrics Publications

Chondrosarcomas are the second most common cause of bone cancer and are removed surgically with wide margins. On recurrence, they are resistant to chemo and radiation therapy and new treatment options are critically required. This tumor type produces hyaline cartilage, a cartilage normally formed under hypoxic and acidic environment due to lack of vasculature in cartilage. Paradoxically, chondrosarcomas arise in the well vascularized, oxygen rich environment of the bone. Hypoxia and acidosis are two stressors where the cellular effects are typically reported separately even though cells experience combined effects of hypoxia and acidosis. Given the mechanistic links between hypoxia and …

Assessing The Roles Of Myc And Egr1 In Endoderm Differentiation, Sadaf R. Shahebrahimi, Joseph Nguyen, Kyra Skye Thomas, Erick Spears

Science University Research Symposium (SURS)

The Wnt signaling pathway is evolutionarily conserved from fruit flies to humans. Strongly associated with development and embryonic morphogenesis, it is known to be required for early endoderm and later hindgut development in mammals. In adults, the Wnt signaling pathway is required for the proper maintenance of the intestinal epithelium and mutations in critical Wnt signaling pathway components are initiating events in the development of essentially all colorectal cancers. An important target gene whose expression is upregulated by Wnt signaling pathway activation is the oncogene MYC. This gene produces a transcription factor whose typical cellular role is to stimulate …

Enhancing The Conformational Stability Of The Cl-Par-4 Tumor Suppressor Via Site-Directed Mutagenesis, Samjhana Pandey, Krishna K. Raut, Andrea M. Clark, Antoine Baudin, Lamya Djemri, David S. Libich, Komala Ponniah, Steven M. Pascal

Chemistry & Biochemistry Faculty Publications

Intrinsically disordered proteins play important roles in cell signaling, and dysregulation of these proteins is associated with several diseases. Prostate apoptosis response-4 (Par-4), an approximately 40 kilodalton proapoptotic tumor suppressor, is a predominantly intrinsically disordered protein whose downregulation has been observed in various cancers. The caspase-cleaved fragment of Par-4 (cl-Par-4) is active and plays a role in tumor suppression by inhibiting cell survival pathways. Here, we employed site-directed mutagenesis to create a cl-Par-4 point mutant (D313K). The expressed and purified D313K protein was characterized using biophysical techniques, and the results were compared to that of the wild-type (WT). We have …