Instructed-Assembly as Context-Dependent Nanoscale Signals for Death and Morphogenesis of Cells

2019 ◽  
Author(s):  
Huaimin Wang ◽  
Zhaoqianqi Feng ◽  
Bing Xu
Keyword(s):  
Cell Death ◽  
Enzyme Activity ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Drug Screening ◽  
Cell Behavior ◽  
Biological Functions ◽  
Cell Spheroids ◽  
Cellular Environment ◽  
Context Dependent

Context-dependent signaling, as a ubiquitous phenomenon in nature, is a dynamic molecular process at nano- and microscales, but how to mimic its essence using non-covalent synthesis in cellular environment has yet to be developed. Here we show a dynamic continuum of non-covalent filaments formed by instructed-assembly (iA) of a supramolecular phosphoglycopeptide (sPGP) as context-dependent signals for controlling death and morphogenesis of cells. Specifically, while enzymes (i.e., ectophosphatases) on cancer cells catalyze the formation of the filaments of the sPGP to result in cell death, damping the enzyme activity induces 3D cell spheroids. Similarly, relying on the ratio of stromal and cancer cells in a co-culture to modulate the expression of the ectophosphatase, the iA process enables cell spheroids. The spheroids act as a mimic of tumor microenvironment for drug screening. As the first demonstration of iA as multifunctional processes according to local enzyme activity for controlling cell behavior, this work illustrates context-dependent biological functions of non-covalent synthesis in cellular environment.

Instructed-Assembly as Context-Dependent Nanoscale Signals for Death and Morphogenesis of Cells

2019 ◽  
Author(s):  
Huaimin Wang ◽  
Zhaoqianqi Feng ◽  
Bing Xu
Keyword(s):  
Cell Death ◽  
Enzyme Activity ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Drug Screening ◽  
Cell Behavior ◽  
Biological Functions ◽  
Cell Spheroids ◽  
Cellular Environment ◽  
Context Dependent

Context-dependent signaling, as a ubiquitous phenomenon in nature, is a dynamic molecular process at nano- and microscales, but how to mimic its essence using non-covalent synthesis in cellular environment has yet to be developed. Here we show a dynamic continuum of non-covalent filaments formed by instructed-assembly (iA) of a supramolecular phosphoglycopeptide (sPGP) as context-dependent signals for controlling death and morphogenesis of cells. Specifically, while enzymes (i.e., ectophosphatases) on cancer cells catalyze the formation of the filaments of the sPGP to result in cell death, damping the enzyme activity induces 3D cell spheroids. Similarly, relying on the ratio of stromal and cancer cells in a co-culture to modulate the expression of the ectophosphatase, the iA process enables cell spheroids. The spheroids act as a mimic of tumor microenvironment for drug screening. As the first demonstration of iA as multifunctional processes according to local enzyme activity for controlling cell behavior, this work illustrates context-dependent biological functions of non-covalent synthesis in cellular environment.

scholarly journals Oncogenic signaling inhibits c-FLIPL expression and its non-apoptotic function during ECM-detachment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Matyas Abel Tsegaye ◽  
Jianping He ◽  
Kyle McGeehan ◽  
Ireland M. Murphy ◽  
Mati Nemera ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Protein C ◽  
Tumor Tissue ◽  
Oncogenic Signaling ◽  
Inhibitory Protein ◽  
Cell Death Pathways ◽  
Apoptotic Protein ◽  
Cellular Context ◽  
Context Dependent

AbstractInhibition of programmed cell death pathways is frequently observed in cancer cells where it functions to facilitate tumor progression. However, some proteins involved in the regulation of cell death function dichotomously to both promote and inhibit cell death depending on the cellular context. As such, understanding how cell death proteins are regulated in a context-dependent fashion in cancer cells is of utmost importance. We have uncovered evidence that cellular FLICE-like Inhibitory Protein (c-FLIP), a well-known anti-apoptotic protein, is often downregulated in tumor tissue when compared to adjacent normal tissue. These data argue that c-FLIP may have activity distinct from its canonical role in antagonizing cell death. Interestingly, we have discovered that detachment from extracellular matrix (ECM) serves as a signal to elevate c-FLIP transcription and that oncogenic signaling blocks ECM-detachment-induced c-FLIP elevation. In addition, our data reveal that downregulation of c-FLIP promotes luminal filling in mammary acini and that c-FLIP overexpression in cancer cells inhibits colony formation in cells exposed to ECM-detachment. Taken together, our study reveals an unexpected, non-apoptotic role for c-FLIP during ECM-detachment and raises the possibility that c-FLIP may have context-dependent roles during tumorigenesis.

scholarly journals Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces autophagic cell death via inhibiting mTOR

2021 ◽  
Author(s):  
Boah Lee ◽  
Seung Ju Park ◽  
Seulgi Lee ◽  
Jinwook Lee ◽  
Eun Byeol Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Therapeutic Option ◽  
Cholesterol Lowering ◽  
Cellular Environment ◽  
Lowering Drug

Autophagy is a biological process that maintains cellular homeostasis and regulates the internal cellular environment. Hyperactivating autophagy to trigger cell death has been a suggested therapeutic strategy for cancer treatment. Mechanistic target of rapamycin (mTOR) is a crucial protein kinase that regulates autophagy; therefore, using a structure-based virtual screen analysis, we identified lomitapide, a cholesterol-lowering drug, as a potential mTOR complex 1 (mTORC1) inhibitor. Our results showed that lomitapide directly inhibits mTORC1 in vitro and induces autophagy-dependent cancer cell death by decreasing mTOR signaling, thereby inhibiting the downstream events associated with increased LC3 conversion in various cancer cells (e.g., HCT116 colorectal cancer cells) and tumor xenografts. Lomitapide also significantly suppresses the growth and viability along with elevated autophagy in patient-derived colorectal cancer organoids. Furthermore, a combination of lomitapide and immune checkpoint blocking antibodies synergistically inhibits tumor growth in murine MC-38 or B16-F10 pre-clinical syngeneic tumor models. These results elucidates the direct, tumor-relevant immune-potentiating benefits of mTORC1 inhibition by lomitapide, which complement the current immune checkpoint blockade. This study highlights the potential repurposing of lomitapide as a new therapeutic option for cancer treatment.

scholarly journals Oncogenic signaling inhibits c-FLIP expression and promotes cancer cell survival during ECM-detachment

2021 ◽  
Author(s):  
Matyas Abel Tsegaye ◽  
Jianping He ◽  
Kyle McGeehan ◽  
Ireland M. Murphy ◽  
Mati Nemera ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Protein C ◽  
Oncogenic Signaling ◽  
Inhibitory Protein ◽  
Cell Death Pathways ◽  
Apoptotic Protein ◽  
Cancer Cell Survival ◽  
Cellular Context ◽  
Context Dependent

AbstractInhibition of programmed cell death pathways is frequently observed in cancer cells where it functions to facilitate tumor progression. However, some proteins involved in the regulation of cell death function dichotomously to both promote and inhibit cell death depending on the cellular context. As such, understanding how cell death proteins are regulated in a context-dependent fashion in cancer cells is of utmost importance. We have uncovered evidence that cellular FLICE-like Inhibitory Protein (c-FLIP), a well-known anti-apoptotic protein, is often downregulated in tumor tissue when compared to adjacent normal tissue. These data argue that c-FLIP may have activity distinct from its canonical role in antagonizing cell death. Interestingly, we have discovered that detachment from extracellular matrix (ECM) serves as a signal to elevate c-FLIP transcription and that oncogenic signaling blocks ECM-detachment-induced c-FLIP elevation. In addition, our data reveal that downregulation of c-FLIP promotes the survival of ECM-detached cells and that c-FLIP overexpression in cancer cells restricts the viability of cancer cells grown in anchorage-independent conditions. Taken together, our study reveals an unexpected role for c-FLIP in constraining the viability of cancer cells during ECM-detachment and raises the idea that c-FLIP may have context-dependent pro- and anti-cell death roles during tumorigenesis.

scholarly journals Ligand-Targeted Delivery of Photosensitizers for Cancer Treatment

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5317
Author(s):  
Piotr Gierlich ◽  
Ana I. Mata ◽  
Claire Donohoe ◽  
Rui M. M. Brito ◽  
Mathias O. Senge ◽  
...  
Keyword(s):  
Cell Death ◽  
Photodynamic Therapy ◽  
Tumor Microenvironment ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Targeted Delivery ◽  
Active Targeting ◽  
Cell Internalization ◽  
Tumor Accumulation ◽  
Skin Photosensitivity

Photodynamic therapy (PDT) is a promising cancer treatment which involves a photosensitizer (PS), light at a specific wavelength for PS activation and oxygen, which combine to elicit cell death. While the illumination required to activate a PS imparts a certain amount of selectivity to PDT treatments, poor tumor accumulation and cell internalization are still inherent properties of most intravenously administered PSs. As a result, common consequences of PDT include skin photosensitivity. To overcome the mentioned issues, PSs may be tailored to specifically target overexpressed biomarkers of tumors. This active targeting can be achieved by direct conjugation of the PS to a ligand with enhanced affinity for a target overexpressed on cancer cells and/or other cells of the tumor microenvironment. Alternatively, PSs may be incorporated into ligand-targeted nanocarriers, which may also encompass multi-functionalities, including diagnosis and therapy. In this review, we highlight the major advances in active targeting of PSs, either by means of ligand-derived bioconjugates or by exploiting ligand-targeting nanocarriers.

An Aptamer Bio-barCode (ABC) assay using SPR, RNase H, and probes with RNA and gold-nanorods for anti-cancer drug screening

The Analyst ◽  
2017 ◽  
Vol 142 (19) ◽  
pp. 3579-3587 ◽  
Author(s):  
Jacky Fong-Chuen Loo ◽  
Chengbin Yang ◽  
Hing Lun Tsang ◽  
Pui Man Lau ◽  
Ken-Tye Yong ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Gold Nanorods ◽  
Drug Screening ◽  
Rnase H ◽  
Cancer Drug ◽  
Next Generation ◽  
Anti Cancer ◽  
A Cell

We have developed a next generation aptamer-based bio-barcode (ABC) assay to detect cytochrome-c (Cyto-c), a cell death marker released from cancer cells, for anti-cancer drug screening.

scholarly journals Differential expression of efferocytosis and phagocytosis associated genes in tumor associated macrophages exposed to African American patient derived prostate cancer microenvironment

2019 ◽  
Vol 9 (2) ◽  
pp. 22 ◽  
Author(s):  
Hirendra Banerjee ◽  
Christopher Krauss ◽  
Myla Worthington ◽  
Narendra Banerjee ◽  
Ray Shawn Walker ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
African American ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Differential Expression ◽  
Microarray Analysis ◽  
African American Patient ◽  
Tumor Associated Macrophages ◽  
Aberrant Expression ◽  
Cellular Environment

Macrophages are the first line of defense in the cellular environment in response to any antigenic or foreign invasion. Since cancer cells express antigenic molecules and create a tumor microenvironment quite different from the normal cellular environment, macrophages will attack this cancer cells as foreign Invaders. However, the cancer cells adept their ability to suppress macrophage activity by secreting compounds/proteins through unknown mechanisms and train these macrophages to aid in tumorigenesis. These macrophages are commonly known as tumor associated macrophages (TAM). In this study, our goal was to find out key regulatory molecules involved in this conversion of cancer-fighting macrophages to cancer friendly macrophages. We used African American(AA) patient derived established human prostate cancer cells along with the human derived macrophages followed by Affymetrix cDNA microarray analysis. Microarray analysis of the PCa cell exposed macrophages revealed appreciable decrease in mRNA expression of several genes associated with phagocytosis process. Aberrant expression of several noncoding RNAs that control the expression of such phagocytosis associated molecules were also evident. Increased expression of oncogenic miR such as, miR-148, 615, 515, 130, 139 and markedly decreased expression of tumor suppressive miR’s MiR-3130, let7c,101,103, 383 were noted. Further, TARGET SCAN analysis demonstrated these differential expression of non-coding RNA’s causing down regulation of phagocytosis promoting genes elf5A, Meg3, Tubb5, Sparcl-1, Uch-1, Bsg(CD147), Ube2v, GULP, Stabilin 1 and Pamr1. There is an increase of RAP1GAP gene that causes concomitant decrease in the expression of tubulin genes that promote cytoskeletal assembly in forming phagosomes. In addition Ingenuity pathway analysis of the gene expression data also showed upregulation of antiphagocytic genes IL-10, CD16, IL-18 and MMP-9. Some core canonical pathways showing physiology of cellular signaling obtained by data analyzed by the Ingenuity software is confirmed a very complex mechanism still to be deciphered involved in the biology of TAM formation by which the rogue cancer cells tame their enemies, the macrophages and actually make them their helper cells to survive and propagate in the tumor microenvironment and thus prepare for epithelial mesenchymal transition for future metastasis and cancer stem cell formation and progression.

scholarly journals In vitro hyperthermic effect of magnetic fluid on cervical and breast cancer cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Anand Bhardwaj ◽  
Kinnari Parekh ◽  
Neeraj Jain
Keyword(s):  
Breast Cancer ◽  
Magnetic Field ◽  
Cell Death ◽  
Cancer Cells ◽  
Magnetic Fluid ◽  
Trypan Blue ◽  
Blue Dye ◽  
Cellular Environment ◽  
Zn Ferrite ◽  
The Magnetic Field

Abstract Self-regulating temperature-controlled nanoparticles such as Mn–Zn ferrite nanoparticles based magnetic fluid can be a better choice for magnetic fluid hyperthermia because of its controlled regulation of hyperthermia temperature window of 43–45 °C. To test this hypothesis magnetic fluid with said properties was synthesized, and its effect on cervical and breast cancer cell death was studied. We found that the hyperthermia window of 43–45 °C was maintained for one hour at the smallest possible concentration of 0.35 mg/mL without altering the magnetic field applicator parameters. Their hyperthermic effect on HeLa and MCF7 was investigated at the magnetic field of 15.3 kA/m and frequency 330 kHz, which is close to the upper safety limit of 5 * 109 A/m s. We have tested the cytotoxicity of synthesized Mn–Zn ferrite fluid using MTT assay and the results were validated by trypan blue dye exclusion assay that provides the naked eye microscopic view of actual cell death. Since cancer cells tend to resist treatment and show re-growth, we also looked into the effect of multiple sessions hyperthermia using a 24 h window till 72 h using trypan blue assay. The multiple sessions of hyperthermia showed promising results, and it indicated that a minimum of 3 sessions, each of one-hour duration, is required for the complete killing of cancer cells. Moreover, to simulate an in vivo cellular environment, a phantom consisting of magnetic nanoparticles dispersed in 1 and 5% agarose gel was constituted and studied. These results will help to decide the magnetic fluid based hyperthermic therapeutic strategies using temperature-sensitive magnetic fluid.

scholarly journals H-1 Parvovirus as a Cancer-Killing Agent: Past, Present, and Future

Viruses ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 562 ◽  
Author(s):  
Clemens Bretscher ◽  
Antonio Marchini
Keyword(s):  
Overall Survival ◽  
Cell Death ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Cancer Cells ◽  
Tumor Bed ◽  
Anticancer Properties ◽  
Cell Death Pathways ◽  
Cancer Cell Death ◽  
Virus Distribution

The rat protoparvovirus H-1PV is nonpathogenic in humans, replicates preferentially in cancer cells, and has natural oncolytic and oncosuppressive activities. The virus is able to kill cancer cells by activating several cell death pathways. H-1PV-mediated cancer cell death is often immunogenic and triggers anticancer immune responses. The safety and tolerability of H-1PV treatment has been demonstrated in early clinical studies in glioma and pancreatic carcinoma patients. Virus treatment was associated with surrogate signs of efficacy including immune conversion of tumor microenvironment, effective virus distribution into the tumor bed even after systemic administration, and improved patient overall survival compared with historical control. However, monotherapeutic use of the virus was unable to eradicate tumors. Thus, further studies are needed to improve H-1PV’s anticancer profile. In this review, we describe H-1PV’s anticancer properties and discuss recent efforts to improve the efficacy of H-1PV and, thereby, the clinical outcome of H-1PV-based therapies.

scholarly journals Salubrinal Exposes Anticancer Properties in Inflammatory Breast Cancer Cells by Manipulating the Endoplasmic Reticulum Stress Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Andrew Alsterda ◽  
Kumari Asha ◽  
Olivia Powrozek ◽  
Miroslava Repak ◽  
Sudeshna Goswami ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Tumor Microenvironment ◽  
Er Stress ◽  
Cancer Cells ◽  
Inflammatory Breast Cancer ◽  
Caspase 3 ◽  
Binding Protein

The endoplasmic reticulum (ER) regulates protein folding, post-translational modifications, lipid synthesis, and calcium signaling to attenuate the accumulation of misfolded proteins causing ER stress and maintains cellular homeostasis. The tumor microenvironment is rich in soluble cytokines, chemokines, growth, and angiogenic factors and can drive the ER’s abnormal functioning in healthy cells. Cancer cells adapt well to the tumor microenvironment induced ER stress. We identified that the inflammatory breast cancer (IBC) cells abundantly express osteoprotegerin (OPG) and their tumor microenvironment is rich in OPG protein. OPG also called osteoclast differentiation factor/osteoclastogenesis inhibitory factor (OCIF) is a soluble decoy receptor for receptor activator of nuclear factor-kappa B ligand (RANKL). Employing mass spectrometry analysis, we identified a set of ER chaperones associated with OPG in IBC cell lysates (SUM149PT, SUM1315MO2) compared to healthy human mammary epithelial cells (HMEC). Proximity ligation assay (PLA) and immunoprecipitation assay validated the interaction between OPG and ER chaperone and master regulator of unfolded protein response (UPR) GRP78/BiP (glucose-regulated protein/Binding immunoglobulin protein). We detected remarkably high gene expression of CCAAT enhancer-binding protein homologous protein (CHOP), inositol-requiring enzyme 1 (IRE1α), protein disulfide-isomerase (PDI), PKR-like ER kinase (PERK), activating transcription factor 4 (ATF4), X-box binding protein 1 (XBP-1) and growth arrest and DNA damage-inducible protein (GADD34) in SUM149PT and SUM190PT cells when compared to HMEC. Similarly, tissue sections of human IBC expressed high levels of ER stress proteins. We evaluated cell death and apoptosis upon Salubrinal and phenylbutyrate treatment in healthy and IBC cells by caspase-3 activity and cleaved poly (ADP-ribose) polymerase (PARP) protein assay. IBC (SUM149PT and SUM190PT) cells were chemosensitive to Salubrinal treatment, possibly via inhibition in OPG secretion, upregulating ATF4, and CHOP, thus ultimately driving caspase-3 mediated IBC cell death. Salubrinal treatment upregulated PDI, which connects ER stress to oxidative stress. We observed increased ROS production and reduced cell proliferation of Salubrinal treated IBC cells. Treatment with antioxidants could rescue IBC cells from ROS and aborted cell proliferation. Our findings implicate that manipulating ER stress with Salubrinal may provide a safer and tailored strategy to target the growth of inflammatory and aggressive forms of breast cancer.

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