Inhibition of human glioblastoma cell invasion involves PION@E6 mediated autophagy process

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Abstract

Background

Glioblastoma (GBM) is the most severe brain cancer due to its ability to invade surrounding brain tissue. Iron oxide nanoparticles (ION) could effectively induce a decrease of cell migration/invasion. Also IONs could generate ROS stress which induces autophagy elevation. Autophagy is associated with both anti-tumorigenesis and protumorigenesis.

Objective

To explore the effect of PEGylated IONs (PION@E6) on the GBM cell invasion and its mechanism based on autophagy.

Materials and methods

PION@E6 were prepared and characterized according to our previous study. After incubation of U251 cells with PION@E6, cellular uptake of PION@E6 and cell viability were tested by Prussian blue staining and Cell Counting Kit-8, respectively. The migration and invasive capability was assessed by transwell cell migration and invasion assay. Expressions of autophagy biomarkers were detected by Western blotting. Intracellular ROS level was determined using 2′–7′-dichlorodihydrofluorescein diacetate.

Results

Average hydrate particle size and zeta potential of PION@E6 were 37.86±12.90 nm and –23.8 mV, respectively, and uniformly distributed nanoparticles with an average diameter of 10 nm were observed by TEM. Chlorin e6 successfully incorporated onto PION@E6 was demonstrated by ultraviolet and visible absorption spectrophotometry, and PION@E6 owning excellent water solubility and stability were showed by Colloid stability test. PION@E6 were successfully taken up by U251 cells with Prussian blue staining, and they showed in vitro cytotoxicity to glioma cells after long incubation of 72 hours. Migration/invasion of cells was significantly inhibited by PION@E6, which could be counteracted by pretreatment with 3-MA. Additionally, the expression of beclin-1, IC3I, and IC3II proteins was higher, whereas that of p62 protein was lower. Moreover, a dose dependent intracellular ROS generation of PION@E6 was detected.

Conclusion

Invasiveness of human GBM cells involves the PION@E6-mediated autophagy process, which may be related to the intracellular ROS induced by PION@E6.

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Most cited references 23

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Guidelines for the use and interpretation of assays for monitoring autophagy.

C N Estevez, S M Lee, Qing Zhong … (2012)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

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Pancreatic cancers require autophagy for tumor growth.

Shenghong Yang, Xiaoxu Wang, Gianmarco Contino … (2011)

Macroautophagy (autophagy) is a regulated catabolic pathway to degrade cellular organelles and macromolecules. The role of autophagy in cancer is complex and may differ depending on tumor type or context. Here we show that pancreatic cancers have a distinct dependence on autophagy. Pancreatic cancer primary tumors and cell lines show elevated autophagy under basal conditions. Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species, elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation. Together, these ultimately result in significant growth suppression of pancreatic cancer cells in vitro. Most importantly, inhibition of autophagy by genetic means or chloroquine treatment leads to robust tumor regression and prolonged survival in pancreatic cancer xenografts and genetic mouse models. These results suggest that, unlike in other cancers where autophagy inhibition may synergize with chemotherapy or targeted agents by preventing the up-regulation of autophagy as a reactive survival mechanism, autophagy is actually required for tumorigenic growth of pancreatic cancers de novo, and drugs that inactivate this process may have a unique clinical utility in treating pancreatic cancers and other malignancies with a similar dependence on autophagy. As chloroquine and its derivatives are potent inhibitors of autophagy and have been used safely in human patients for decades for a variety of purposes, these results are immediately translatable to the treatment of pancreatic cancer patients, and provide a much needed, novel vantage point of attack.

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Interplay between ROS and autophagy in cancer cells, from tumor initiation to cancer therapy

Laura Poillet-Perez, Gilles Despouy, Régis Delage-Mourroux … (2014)

Cancer formation is a complex and highly regulated multi-step process which is highly dependent of its environment, from the tissue to the patient. This complexity implies the development of specific treatments adapted to each type of tumor. The initial step of cancer formation requires the transformation of a healthy cell to a cancer cell, a process regulated by multiple intracellular and extracellular stimuli. The further steps, from the anarchic proliferation of cancer cells to form a primary tumor to the migration of cancer cells to distant organs to form metastasis, are also highly dependent of the tumor environment but of intracellular molecules and pathways as well. In this review, we will focus on the regulatory role of reactive oxygen species (ROS) and autophagy levels during the course of cancer development, from cellular transformation to the formation of metastasis. These data will allow us to discuss the potential of this molecule or pathway as putative future therapeutic targets.

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Author and article information

Journal

Journal ID (nlm-ta): Cancer Manag Res

Journal ID (iso-abbrev): Cancer Manag Res

Journal ID (publisher-id): Cancer Management and Research

Title: Cancer Management and Research

Publisher: Dove Medical Press

ISSN (Electronic): 1179-1322

Publication date Collection: 2019

Publication date (Electronic): 29 March 2019

Volume: 11

Pages: 2643-2652

Affiliations

Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guangxi, People’s Republic of China, wenjian2400@ 123456163.com

Author notes

Correspondence: Jian Wen, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guangxi, 541040, People’s Republic of China, Tel +86 189 9404 3727, Email wenjian2400@ 123456163.com

Article

Publisher ID: cmar-11-2643

DOI: 10.2147/CMAR.S200151

PMC ID: 6446987

SO-VID: 9571ed74-d4c7-4c6d-92bb-813196c8a8f8

License:

The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

Inhibition of human glioblastoma cell invasion involves PION@E6 mediated autophagy process

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Abstract

Background

Objective

Materials and methods

Results

Conclusion

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Cancer Immunotherapy

Most cited references 23

Guidelines for the use and interpretation of assays for monitoring autophagy.

Pancreatic cancers require autophagy for tumor growth.

Interplay between ROS and autophagy in cancer cells, from tumor initiation to cancer therapy

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