Exosomal connexin 43 regulates the resistance of glioma cells to temozolomide

Yang, Zhang‐Jian; Zhang, Le-ling; Bi, Qiu‐Chen; Gan, Lijun; Wei, Minjun; Hong, Tao; Tan, Renjie; Lan, Xue-Mei; Liu, Lihua; Han, Xiao‐Jian; Jiang, Liping

doi:10.3892/or.2021.7995

Cited by 24 publications

(23 citation statements)

References 46 publications

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“…Expression levels of the proteins of interest were examined by Western Blot analysis as previously described 28 . Briefly, cells or the isolated exosomes were harvested and lysed in radioimmunoprecipitation assay (RIPA) buffer (Solarbio, Beijing) with protease inhibitors.…”

Section: Methodsmentioning

confidence: 99%

Exosomes Derived from Glioma Cells under Hypoxia Promote Angiogenesis through Up-regulated Exosomal Connexin 43

Yang¹,

Bi²,

Gan³

et al. 2022

Int. J. Med. Sci.

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Glioblastoma multiform (GBM) is a highly aggressive primary brain tumor. Exosomes derived from glioma cells under a hypoxic microenvironment play an important role in tumor biology including metastasis, angiogenesis and chemoresistance. However, the underlying mechanisms remain to be elucidated. In this study, we aimed to explore the role of connexin 43 on exosomal uptake and angiogenesis in glioma under hypoxia. U251 cells were exposed to 3% oxygen to achieve hypoxia, and the expression levels of HIF-1α and Cx43, involved in the colony formation and proliferation of cells were assessed. Exosomes were isolated by differential velocity centrifugation from U251 cells under normoxia and hypoxia (Nor-Exos and Hypo-Exos), respectively. Immunofluorescence staining, along with assays for CCK-8, tube formation and wound healing along with a transwell assay were conducted to profile exosomal uptake, proliferation, tube formation, migration and invasion of HUVECs, respectively. Our results revealed that Hypoxia significantly up-regulated the expression of HIF-1α in U251 cells as well as promoting proliferation and colony number. Hypoxia also increased the level of Cx43 in U251 cells and in the exosomes secreted. The uptake of Dio-stained Hypo-Exos by HUVECs was greater than that of Nor-Exos, and inhibition of Cx43 by 37,43 gap27 or lenti-Cx43-shRNA efficiently prevented the uptake of Hypo-Exos by recipient endothelial cells. In addition, the proliferation and total loops of HUVECs were remarkably increased at 24 h, 48 h, and 10 h after Hypo-Exos, respectively. Notably, 37,43 gap27, a specific Cx-mimetic peptide blocker of Cx37 and Cx43, efficiently alleviated Hypo-Exos-induced proliferation and tube formation by HUVECs. Finally, 37,43 gap27 also significantly attenuated Hypo-Exos-induced migration and invasion of HUVECs. These findings demonstrate that exosomal Cx43 contributes to glioma angiogenesis mediated by Hypo-Exos, and suggests that exosomal Cx43 might serve as a potential therapeutic target for glioblastoma.

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Section: Methodsmentioning

confidence: 99%

Exosomes Derived from Glioma Cells under Hypoxia Promote Angiogenesis through Up-regulated Exosomal Connexin 43

Yang¹,

Bi²,

Gan³

et al. 2022

Int. J. Med. Sci.

Self Cite

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“…Expression levels of exosome-linked protein 43 (Cx43) were significantly higher in TMZ-resistant GBM cells compared with TMZ-sensitive cells. Exosome-derived Cx43 from TMZ-resistant GBM cells significantly enhanced cell migration and invasion and conferred TMZ resistance to receptor-sensitive cells, suggesting that Cx43 is expected to be a future therapeutic target for glioblastoma [ 92 ]. EV secreted by Glioma stem cells (GSC-EV) could be involved in radiation resistance and malignant progression of glioma.…”

Section: The Roles Of Texs In Chemoresistancementioning

confidence: 99%

Tumor-derived small extracellular vesicles: potential roles and mechanism in glioma

2022

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Small extracellular vesicles (SEVs) are extracellular vesicles containing DNA, RNA, and proteins and are involved in intercellular communication and function, playing an essential role in the growth and metastasis of tumors. SEVs are present in various body fluids and can be isolated and extracted from blood, urine, and cerebrospinal fluid. Under both physiological and pathological conditions, SEVs can be released by some cells, such as immune, stem, and tumor cells, in a cytosolic manner. SEVs secreted by tumor cells are called tumor-derived exosomes (TEXs) because of their origin in the corresponding parent cells. Glioma is the most common intracranial tumor, accounting for approximately half of the primary intracranial tumors, and is characterized by insidious onset, high morbidity, and high mortality rate. Complete removal of tumor tissues by surgery is difficult. Chemotherapy can improve the survival quality of patients to a certain extent; however, gliomas are prone to chemoresistance, which seriously affects the prognosis of patients. In recent years, TEXs have played a vital role in the occurrence, development, associated immune response, chemotherapy resistance, radiation therapy resistance, and metastasis of glioma. This article reviews the role of TEXs in glioma progression, drug resistance, and clinical diagnosis.

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“…Another membrane structure that Cx43 has been detected on is the extracellular vesicles (EV), although some papers referred to them as the more specific EV population of exosomes [ 101 , 102 , 103 , 104 , 105 , 106 ]. In fact, exosomes are a subset of extracellular vesicles that have been defined based on their size, biogenesis, and contents; they are used by cells to achieve communication with other cells that are nearby or even at a great distance (reviewed in [ 107 , 108 ]).…”

Section: Channel-independent Functions Of Cx43 On Plasma Membranementioning

confidence: 99%

Gap Junction-Dependent and -Independent Functions of Connexin43 in Biology

Zhu

2022

Biology

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For the first time in animal evolution, the emergence of gap junctions allowed direct exchanges of cellular substances for communication between two cells. Innexin proteins constituted primordial gap junctions until the connexin protein emerged in deuterostomes and took over the gap junction function. After hundreds of millions of years of gene duplication, the connexin gene family now comprises 21 members in the human genome. Notably, GJA1, which encodes the Connexin43 protein, is one of the most widely expressed and commonly studied connexin genes. The loss of Gja1 in mice leads to swelling and a blockage of the right ventricular outflow tract and death of the embryos at birth, suggesting a vital role of Connexin43 gap junction in heart development. Since then, the importance of Connexin43-mediated gap junction function has been constantly expanded to other types of cells. Other than forming gap junctions, Connexin43 can also form hemichannels to release or uptake small molecules from the environment or even mediate many physiological processes in a gap junction-independent manner on plasma membranes. Surprisingly, Connexin43 also localizes to mitochondria in the cell, playing important roles in mitochondrial potassium import and respiration. At the molecular level, Connexin43 mRNA and protein are processed with very distinct mechanisms to yield carboxyl-terminal fragments with different sizes, which have their unique subcellular localization and distinct biological activities. Due to many exciting advancements in Connexin43 research, this review aims to start with a brief introduction of Connexin43 and then focuses on updating our knowledge of its gap junction-independent functions.

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Exosomal connexin 43 regulates the resistance of glioma cells to temozolomide

Cited by 24 publications

References 46 publications

Exosomes Derived from Glioma Cells under Hypoxia Promote Angiogenesis through Up-regulated Exosomal Connexin 43

Exosomes Derived from Glioma Cells under Hypoxia Promote Angiogenesis through Up-regulated Exosomal Connexin 43

Tumor-derived small extracellular vesicles: potential roles and mechanism in glioma

Gap Junction-Dependent and -Independent Functions of Connexin43 in Biology

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