Mutation of the Conserved Threonine 8 within the Human ARF Tumour Suppressor Protein Regulates Autophagy

Background: The ARF tumour suppressor plays a well-established role as a tumour suppressor, halting cell growth by both p53-dependent and independent pathways in several cellular stress response circuits. However, data collected in recent years challenged the traditional role of this protein as a tumour suppressor. Cancer cells expressing high ARF levels showed that its expression, far from being dispensable, is required to guarantee tumour cell survival. In particular, ARF can promote autophagy, a self-digestion pathway that helps cells cope with stressful growth conditions arising during both physiological and pathological processes. Methods: We previously showed that ARF is regulated through the activation of the protein kinase C (PKC)-dependent pathway and that an ARF phospho-mimetic mutant on the threonine residue 8, ARF-T8D, sustains cell proliferation in HeLa cells. We now explored the role of ARF phosphorylation in both basal and starvation-induced autophagy by analysing autophagic flux in cells transfected with either WT and ARF phosphorylation mutants by immunoblot and immunofluorescence. Results: Here, we show that endogenous ARF expression in HeLa cells is required for starvation-induced autophagy. Further, we provide evidence that the hyper-expression of ARF-T8D appears to inhibit autophagy in both HeLa and lung cancer cells H1299. This effect is due to the cells’ inability to elicit autophagosomes formation upon T8D expression. Conclusions: Our results lead to the hypothesis that ARF phosphorylation could be a mechanism through which the protein promotes or counteracts autophagy. Several observations underline how autophagy could serve a dual role in cancer progression, either protecting healthy cells from damage or aiding cancerous cells to survive. Our results indicate that ARF phosphorylation controls protein’s ability to promote or counteract autophagy, providing evidence of the dual role played by ARF in cancer progression.

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Gadolinium Oxide Nanoparticles Enhance the Cytotoxicity of Chemotherapeutic Drugs by Blocking Autophagic Flux in Human Ovarian Cancer Cells

Current Nanoscience ◽

10.2174/1573413716666200313155239 ◽

2020 ◽

Vol 16 ◽

Author(s):

Zhixiong Xie ◽

Tianyu Zhang ◽

Cheng Zhong

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Hela Cells ◽

Late Stage ◽

Ovarian Cancer Cells ◽

Oxide Nanoparticles ◽

Autophagic Flux ◽

Human Ovarian Cancer ◽

Chemotherapeutic Drugs ◽

Chemotherapy Drugs

Background: During chemotherapy, drugs can damage cancer cells’ DNA and cytomembrane structure, and then induce cell death. However, autophagy can increase the chemotherapy resistance of cancer cells, reducing the effect of chemotherapy. Objective: To block the autophagic flux in cancer cells, it is vital to enhance the anti-cancer efficacy of chemotherapy drugs; for this purpose, we test the gadolinium oxide nanoparticles (Gd2O3 NPs)’ effect on autophagy. Methods: The cytotoxicity of Gd2O3 NPs on HeLa cells was evaluated by a (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Then, monodasylcadaverine staining, immunofluorescence, immunoblot and apoptosis assay were conducted to evaluate the effect of Gd2O3 NPs on autophagy and efficacy of chemotherapy drugs in human ovarian cancer cells. Results: We found that Gd2O3 NPs, which have great potential for use as a contrast agent in magnetic resonance imaging, could block the late stage of autophagic flux in a dose-dependent manner and then cause autophagosome accumulation in HeLa cells. When co-treated with 8 μg/mL Gd2O3 NPs and 5 μg/mL cisplatin, the number of dead HeLa cells increased by about 20% compared with cisplatin alone. We observed the same phenomenon in cisplatin-resistant COC1/DDP cells. Conclusion: We conclude that Gd2O3 NPs can block the late stage of autophagic flux and enhance the cytotoxicity of chemotherapeutic drugs in human ovarian cancer cells. Thus, the nanoparticles have significant potential for use in both diagnosis and therapy of solid tumor.

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A control engineering approach to understanding the TGF-β paradox in cancer

Journal of The Royal Society Interface ◽

10.1098/rsif.2011.0799 ◽

2011 ◽

Vol 9 (71) ◽

pp. 1389-1397 ◽

Cited By ~ 11

Author(s):

Seung-Wook Chung ◽

Carlton R. Cooper ◽

Mary C. Farach-Carson ◽

Babatunde A. Ogunnaike

Keyword(s):

Cancer Cells ◽

Mechanistic Model ◽

Tumour Suppressor ◽

Cancer Tissue ◽

Control Engineering ◽

Cellular Processes ◽

Proliferation And Apoptosis ◽

High Level ◽

Quantitative Explanation

TGF-β, a key cytokine that regulates diverse cellular processes, including proliferation and apoptosis, appears to function paradoxically as a tumour suppressor in normal cells, and as a tumour promoter in cancer cells, but the mechanisms underlying such contradictory roles remain unknown. In particular, given that this cytokine is primarily a tumour suppressor, the conundrum of the unusually high level of TGF-β observed in the primary cancer tissue and blood samples of cancer patients with the worst prognosis, remains unresolved. To provide a quantitative explanation of these paradoxical observations, we present, from a control theory perspective, a mechanistic model of TGF-β-driven regulation of cell homeostasis. Analysis of the overall system model yields quantitative insight into how cell population is regulated, enabling us to propose a plausible explanation for the paradox: with the tumour suppressor role of TGF-β unchanged from normal to cancer cells, we demonstrate that the observed increased level of TGF-β is an effect of cancer cell phenotypic progression (specifically, acquired TGF-β resistance), not the cause . We are thus able to explain precisely why the clinically observed correlation between elevated TGF-β levels and poor prognosis is in fact consistent with TGF-β's original (and unchanged) role as a tumour suppressor.

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Dual role of endothelial cell signaling in cancer progression

Annals of Oncology ◽

10.1093/annonc/mdv120.05 ◽

2015 ◽

Vol 26 ◽

pp. iii29

Author(s):

D.A. Ferraro ◽

R. Goosen ◽

F. Patella ◽

S. Zanivan ◽

M. Buess ◽

...

Keyword(s):

Endothelial Cell ◽

Cell Signaling ◽

Cancer Progression ◽

Dual Role

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How Antimalarials and Antineoplastic Drugs can Interact in Combination Therapies: a Perspective on the Role of PPT1 Enzyme

Current Drug Metabolism ◽

10.2174/1389200222666211118114057 ◽

2021 ◽

Vol 22 ◽

Author(s):

Diana Duarte ◽

Nuno Vale

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Antineoplastic Agents ◽

Antimalarial Drugs ◽

Antineoplastic Drugs ◽

Anticancer Effects ◽

Different Types ◽

Important Pathway ◽

Palmitoyl Protein Thioesterase

: Antimalarial drugs from different classes have demonstrated anticancer effects in different types of cancer cells, but their complete mode of action in cancer remains unknown. Recently, several studies reported the important role of palmitoyl-protein thioesterase 1 (PPT1), a lysosomal enzyme, as the molecular target of chloroquine and its derivates in cancer. It was also found that PPT1 is overexpressed in different types of cancer, such as breast, colon, etc. Our group has found a synergistic interaction between antimalarial drugs, such as mefloquine, artesunate and chloroquine and antineoplastic drugs in breast cancer cells, but the mechanism of action was not determined. Here, we describe the importance of autophagy and lysosomal inhibitors in tumorigenesis and hypothesize that other antimalarial agents besides chloroquine could also interact with PPT1 and inhibit the mechanistic target of rapamycin (mTOR) signalling, an important pathway in cancer progression. We believe that PPT1 inhibition results in changes in the lysosomal metabolism that result in less accumulation of antineoplastic drugs in lysosomes, which increases the bioavailability of the antineoplastic agents. Taken together, these mechanisms help to explain the synergism of antimalarial and antineoplastic agents in cancer cells.

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Dual role of E-cadherin in cancer cells

Tissue Barriers ◽

10.1080/21688370.2021.2005420 ◽

2021 ◽

Author(s):

Svetlana N. Rubtsova ◽

Irina Y. Zhitnyak ◽

Natalya A. Gloushankova

Keyword(s):

Cancer Cells ◽

Dual Role ◽

E Cadherin

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Role of Integrins in Resistance to Therapies Targeting Growth Factor Receptors in Cancer

Cancers ◽

10.3390/cancers11050692 ◽

2019 ◽

Vol 11 (5) ◽

pp. 692 ◽

Cited By ~ 16

Author(s):

Elisabete Cruz da Silva ◽

Monique Dontenwill ◽

Laurence Choulier ◽

Maxime Lehmann

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Tyrosine Kinases ◽

Treatment Options ◽

Cancer Cell Proliferation ◽

Remarkable Feature ◽

Rtk Signaling ◽

Intracellular Signal ◽

New Treatment

Integrins contribute to cancer progression and aggressiveness by activating intracellular signal transduction pathways and transducing mechanical tension forces. Remarkably, these adhesion receptors share common signaling networks with receptor tyrosine kinases (RTKs) and support their oncogenic activity, thereby promoting cancer cell proliferation, survival and invasion. During the last decade, preclinical studies have revealed that integrins play an important role in resistance to therapies targeting RTKs and their downstream pathways. A remarkable feature of integrins is their wide-ranging interconnection with RTKs, which helps cancer cells to adapt and better survive therapeutic treatments. In this context, we should consider not only the integrins expressed in cancer cells but also those expressed in stromal cells, since these can mechanically increase the rigidity of the tumor microenvironment and confer resistance to treatment. This review presents some of these mechanisms and outlines new treatment options for improving the efficacy of therapies targeting RTK signaling.

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Spatiotemporal pH Heterogeneity as a Promoter of Cancer Progression and Therapeutic Resistance

Cancers ◽

10.3390/cancers11071026 ◽

2019 ◽

Vol 11 (7) ◽

pp. 1026 ◽

Cited By ~ 13

Author(s):

David E. Korenchan ◽

Robert R. Flavell

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Co2 Exchange ◽

Therapeutic Resistance ◽

Slow Time ◽

Phenotypic Changes ◽

Ph Buffering ◽

Available Technology ◽

Kinetics Of

Dysregulation of pH in solid tumors is a hallmark of cancer. In recent years, the role of altered pH heterogeneity in space, between benign and aggressive tissues, between individual cancer cells, and between subcellular compartments, has been steadily elucidated. Changes in temporal pH-related processes on both fast and slow time scales, including altered kinetics of bicarbonate-CO2 exchange and its effects on pH buffering and gradual, progressive changes driven by changes in metabolism, are further implicated in phenotypic changes observed in cancers. These discoveries have been driven by advances in imaging technologies. This review provides an overview of intra- and extracellular pH alterations in time and space reflected in cancer cells, as well as the available technology to study pH spatiotemporal heterogeneity.

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Up-regulation of miRNA-148a inhibits proliferation, invasion, and migration while promoting apoptosis of cervical cancer cells by down-regulating RRS1

Bioscience Reports ◽

10.1042/bsr20181815 ◽

2019 ◽

Vol 39 (5) ◽

Cited By ~ 3

Author(s):

Ying Zhang ◽

Bingmei Sun ◽

Lianbin Zhao ◽

Zhengling Liu ◽

Zonglan Xu ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Cell Line ◽

Hela Cells ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Invasion And Migration ◽

Cervical Cancer Cells ◽

And Migration

Abstract The purpose of the present study is to figure out the role of miRNA-148a (miR-148a) in growth, apoptosis, invasion, and migration of cervical cancer cells by binding to regulator of ribosome synthesis 1 (RRS1). Cervical cancer and adjacent normal tissues, as well as cervical cancer cell line Caski, HeLa, C-33A, and normal cervical epithelial cell line H8 were obtained to detect the expression of miR-148a and RRS1. Relationship between miR-148a and RRS1 expression with clinicopathological characteristics was assessed. The selected Caski and HeLa cells were then transfected with miR-148a mimics, miR-148a inhibitors or RRS1 siRNA to investigate the role of miR-148a and RRS1 on proliferation, apoptosis, colony formation, invasion, and migration abilities of cervical cancer cells. Bioinformatics information and dual luciferase reporter gene assay was for used to detect the targetting relationship between miR-148a and RRS1. Down-regulated miR-148a and up-regulated RRS1 were found in cervical cancer tissues and cells. Down-regulated miR-148a and up-regulated RRS1 are closely related with prognostic factors of cervical cancer. RRS1 was determined as a target gene of miR-148a and miR-148a inhibited RRS1 expression in cervical cancer cells. Up-regulation of miR-148a inhibited cell proliferation, migration, and invasion while promoting apoptosis in Caski and HeLa cells. Our study suggests that miR-148a down-regulates RRS1 expression, thereby inhibiting the proliferation, migration, and invasion while promoting cell apoptosis of cervical cancer cells.

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Vimentin filaments drive migratory persistence in polyploidal cancer cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2011912117 ◽

2020 ◽

Vol 117 (43) ◽

pp. 26756-26765

Author(s):

Botai Xuan ◽

Deepraj Ghosh ◽

Joy Jiang ◽

Rachelle Shao ◽

Michelle R. Dawson

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Structural Integrity ◽

Single Cell Analysis ◽

Critical Role ◽

Critical Function ◽

Rna Knockdown ◽

Interfering Rna ◽

The Impact

Polyploidal giant cancer cells (PGCCs) are multinucleated chemoresistant cancer cells found in heterogeneous solid tumors. Due in part to their apparent dormancy, the effect of PGCCs on cancer progression has remained largely unstudied. Recent studies have highlighted the critical role of PGCCs as aggressive and chemoresistant cancer cells, as well as their ability to undergo amitotic budding to escape dormancy. Our recent study demonstrated the unique biophysical properties of PGCCs, as well as their unusual migratory persistence. Here we unveil the critical function of vimentin intermediate filaments (VIFs) in maintaining the structural integrity of PGCCs and enhancing their migratory persistence. We performed in-depth single-cell analysis to examine the distribution of VIFs and their role in migratory persistence. We found that PGCCs rely heavily on their uniquely distributed and polarized VIF network to enhance their transition from a jammed to an unjammed state to allow for directional migration. Both the inhibition of VIFs with acrylamide and small interfering RNA knockdown of vimentin significantly decreased PGCC migration and resulted in a loss of PGCC volume. Because PGCCs rely on their VIF network to direct migration and to maintain their enlarged morphology, targeting vimentin or vimentin cross-linking proteins could provide a therapeutic approach to mitigate the impact of these chemoresistant cells in cancer progression and to improve patient outcomes with chemotherapy.

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Metabolic cooperation between cancer and non-cancerous stromal cells is pivotal in cancer progression

Tumor Biology ◽

10.1177/1010428318756203 ◽

2018 ◽

Vol 40 (2) ◽

pp. 101042831875620 ◽

Cited By ~ 11

Author(s):

Filipa Lopes-Coelho ◽

Sofia Gouveia-Fernandes ◽

Jacinta Serpa

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Stromal Cells ◽

Inflammatory Cells ◽

Metabolic Adaptation ◽

Metabolic Cooperation ◽

Metabolic Remodeling ◽

Organ Tissue ◽

Cancerous Cells

The way cancer cells adapt to microenvironment is crucial for the success of carcinogenesis, and metabolic fitness is essential for a cancer cell to survive and proliferate in a certain organ/tissue. The metabolic remodeling in a tumor niche is endured not only by cancer cells but also by non-cancerous cells that share the same microenvironment. For this reason, tumor cells and stromal cells constitute a complex network of signal and organic compound transfer that supports cellular viability and proliferation. The intensive dual-address cooperation of all components of a tumor sustains disease progression and metastasis. Herein, we will detail the role of cancer-associated fibroblasts, cancer-associated adipocytes, and inflammatory cells, mainly monocytes/macrophages (tumor-associated macrophages), in the remodeling and metabolic adaptation of tumors.

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