Autophagic flux response and glioblastoma sensitivity to radiation

Mitrakas, Achilleas; Kalamida, Dimitra; Giatromanolaki, Alexandra; Pouliliou, Stamatia; Tsolou, Avgi; Kyranas, Rafail; Koukourakis, Michael I.

doi:10.20892/j.issn.2095-3941.2017.0173

Cited by 15 publications

(7 citation statements)

References 45 publications

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“…Moreover, radiation preferentially activates autophagy in CD133 + cells and increases the levels of the autophagy-related proteins LC3, ATG5, and ATG12 [ 67 ]. The same was found in the radioresistant cell line, in which enhanced autophagic flux and silencing of the LC3A gene sensitized mouse xenografts to radiation [ 68 ]. However, in a study examining the induction of autophagy by radiation and its role in the radioresistance of GSCs, the authors found that GSCs expressed lower levels of autophagy-related protein LC3 and radiation induced a low degree of autophagy in these cells [ 69 ].…”

Section: Radioresistancementioning

confidence: 54%

Role of glioblastoma stem cells in cancer therapeutic resistance: a perspective on antineoplastic agents from natural sources and chemical derivatives

et al. 2021

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Glioblastoma (GBM) is the highest-grade form of glioma, as well as one of the most aggressive types of cancer, exhibiting rapid cellular growth and highly invasive behavior. Despite significant advances in diagnosis and therapy in recent decades, the outcomes for high-grade gliomas (WHO grades III-IV) remain unfavorable, with a median overall survival time of 15–18 months. The concept of cancer stem cells (CSCs) has emerged and provided new insight into GBM resistance and management. CSCs can self-renew and initiate tumor growth and are also responsible for tumor cell heterogeneity and the induction of systemic immunosuppression. The idea that GBM resistance could be dependent on innate differences in the sensitivity of clonogenic glial stem cells (GSCs) to chemotherapeutic drugs/radiation prompted the scientific community to rethink the understanding of GBM growth and therapies directed at eliminating these cells or modulating their stemness. This review aims to describe major intrinsic and extrinsic mechanisms that mediate chemoradioresistant GSCs and therapies based on antineoplastic agents from natural sources, derivatives, and synthetics used alone or in synergistic combination with conventional treatment. We will also address ongoing clinical trials focused on these promising targets. Although the development of effective therapy for GBM remains a major challenge in molecular oncology, GSC knowledge can offer new directions for a promising future.

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Section: Radioresistancementioning

confidence: 54%

Role of glioblastoma stem cells in cancer therapeutic resistance: a perspective on antineoplastic agents from natural sources and chemical derivatives

et al. 2021

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“…There are a large number of investigations that show autophagy as a mechanism that confers protection against the induction of cell death by different antineoplastic agents [ 53 , 54 ], radiotherapy [ 55 ], or endocrine therapy in breast cancer [ 56 , 57 ] to mention a few examples. Despite the discussion, the role of autophagy in cancer is still debatable.…”

Section: Discussionmentioning

confidence: 99%

Negative Regulation of ULK1 by microRNA-106a in Autophagy Induced by a Triple Drug Combination in Colorectal Cancer Cells In Vitro

Salgado-García

Coronel-Hernández

Delgado-Waldo³

et al. 2021

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Colorectal cancer (CRC) is among the top three most deadly cancers worldwide. The survival rate for this disease has not been reduced despite the treatments, the reason why the search for therapeutic alternatives continues to be a priority issue in oncology. In this research work, we tested our successful pharmacological combination of three drugs, metformin, doxorubicin, and sodium oxamate (triple therapy, or TT), as an autophagy inducer. Firstly, we employed western blot (WB) assays, where we observed that after 8 h of stimulation with TT, the proteins Unc-51 like autophagy activating kinase 1(ULK1), becline-1, autophagy related 1 protein (Atg4), and LC3 increased in the CRC cell lines HCT116 and SW480 in contrast to monotherapy with doxorubicin. The overexpression of these proteins indicated the beginning of autophagy flow through the activation of ULK1 and the hyperlipidation of LC3 at the beginning of this process. Moreover, we confirm that ULK1 is a bona fide target of hsa-miR-106a-5p (referred to from here on as miR-106a) in HCT116. We also observed through the GFP-LC3 fusion protein that in the presence of miR-106a, the accumulation of autophagy vesicles in cells stimulated with TT is inhibited. These results show that the TT triggered autophagy to modulate miR-106a/ULK1 expression, probably affecting different cellular pathways involved in cellular proliferation, survivance, metabolic maintenance, and cell death. Therefore, considering the importance of autophagy in cancer biology, the study of miRNAs that regulate autophagy in cancer will allow a better understanding of malignant tumors and lead to the development of new disease markers and therapeutic strategies.

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“… 17 Autophagy plays a vital role in the malignancy, senescence, radioresistance, and chemoresistance of glioma. 30 – 32 It is therefore likely that LMX1B cooperates with NF-κB and E47 to regulate gankyrin expression in glioma patients, and upregulated gankyrin subsequently promotes the malignancy and poor prognosis of glioma by regulating autophagic flux. This hypothesis warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

LMX1B-associated gankyrin expression predicts poor prognosis in glioma patients

et al. 2020

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Objective To explore the potential of the transcription factor LMX1B and downstream gankyrin as prognostic biomarkers of glioma. Methods The expression levels of gankyrin and LMX1B were detected in 52 normal brain specimens and 339 glioma specimens. Correlations of gankyrin and LMX1B expression levels with pathological stages and clinical characteristics were statistically analyzed. Furthermore, the binding of LMX1B to the gankyrin promoter was evaluated using ALGGEN PROMO. Results Levels of LMX1B and gankyrin were significantly increased in tumor tissue, and were significantly associated with advanced glioma grade and poor survival. Compared with gankyrin- and LMX1B-negative glioma, the mean survival of patients with higher gankyrin and LMX1B expression was significantly reduced, from 83.46 to 18.87 months and from 63.79 to 18.29 months, respectively. Furthermore, LMX1B had a moderate positive correlation with gankyrin expression (Pearson’s r = 0.650), and it was also found to act as a transcription factor with NF-κB and E47 on the gankyrin promoter. Conclusions Increased expression of LMX1B and gankyrin has independent prognostic value in glioma patients. The transcription factor LMX1B may have an upstream role in the mechanism of action.

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Autophagic flux response and glioblastoma sensitivity to radiation

Cited by 15 publications

References 45 publications

Role of glioblastoma stem cells in cancer therapeutic resistance: a perspective on antineoplastic agents from natural sources and chemical derivatives

Role of glioblastoma stem cells in cancer therapeutic resistance: a perspective on antineoplastic agents from natural sources and chemical derivatives

Negative Regulation of ULK1 by microRNA-106a in Autophagy Induced by a Triple Drug Combination in Colorectal Cancer Cells In Vitro

LMX1B-associated gankyrin expression predicts poor prognosis in glioma patients

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