Mitochondria’s Role in the Maintenance of Cancer Stem Cells in Glioblastoma
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Glioblastoma (GBM), one of the deadliest primary brain malignancies, is characterized by a high recurrence rate due to its limited response to existing therapeutic strategies such as chemotherapy, radiation therapy, and surgery. Several mechanisms and pathways have been identified to be responsible for GBM therapeutic resistance. Glioblastoma stem cells (GSCs) are known culprits of GBM resistance to therapy. GSCs are characterized by their unique self-renewal, differentiating capacity, and proliferative potential. They form a heterogeneous population of cancer stem cells within the tumor and are further divided into different subpopulations. Their distinct molecular, genetic, dynamic, and metabolic features distinguish them from neural stem cells (NSCs) and differentiated GBM cells. Novel therapeutic strategies targeting GSCs could effectively reduce the tumor-initiating potential, hence, a thorough understanding of mechanisms involved in maintaining GSCs’ stemness cannot be overemphasized. The mitochondrion, a regulator of cellular physiological processes such as autophagy, cellular respiration, reactive oxygen species (ROS) generation, apoptosis, DNA repair, and cell cycle control, has been implicated in various malignancies (for instance, breast, lung, and prostate cancer). Besides, the role of mitochondria in GBM has been extensively studied. For example, when stressors, such as irradiation and hypoxia are present, GSCs utilize specific cytoprotective mechanisms like the activation of mitochondrial stress pathways to survive the harsh environment. Proliferating GBM cells exhibit increased cytoplasmic glycolysis in comparison to terminally differentiated GBM cells and quiescent GSCs that rely more on oxidative phosphorylation (OXPHOS). Furthermore, the Warburg effect, which is characterized by increased tumor cell glycolysis and decreased mitochondrial metabolism in the presence of oxygen, has been observed in GBM. Herein, we highlight the importance of mitochondria in the maintenance of GSCs.Keywords:
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PURPOSE RNF6 is verified to promote the malignant growth of colorectal cancer (CRC) and its level is linked to prognosis in CRC patients. Radioresistance is a key factor influencing prognosis in CRC. This study aimed to uncover the potential regulation of ring finger protein 6 (RNF6) in CRC radioresistance. METHODS RNF6 levels in radioresistant and non-radioresistant CRC patients were detected. In vitro and in vivo regulatory effects of RNF6 on radioresistant CRC cell lines and nude mice bearing radioresistant CRC were examined, respectively. The involvement of Wnt pathway in CRC radioresistance was explored by Western blot. RESULTS RNF6 was highly expressed in radioresistant CRC species than that of non-radioresistant ones. Identically, RNF6 was upregulated in radioresistant CRC cells compared to parental cells. SW1116 cells overexpressing RNF6 were more tolerant to radiotherapy, and similar results were obtained in nude mice bearing radioresistant CRC with overexpression of RNF6. Moreover, the Wnt pathway was activated during RNF6-induced radioresistance improvement in CRC. CONCLUSIONS RNF6 enhances radioresistance of CRC through activating the Wnt pathway.
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// Jiang-Tao Zhong 1 and Shui-Hong Zhou 1 1 Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China Correspondence to: Shui-Hong Zhou, email: // Keywords : hexokinase-II, Warburg effect, laryngeal carcinoma, radioresistance Received : May 20, 2016 Accepted : October 28, 2016 Published : November 03, 2016 Abstract Radiotherapy is now widely used as a part of multidisciplinary treatment approaches for advanced laryngeal carcinoma and preservation of laryngeal function. However, the mechanism of the radioresistance is still unclear. Some studies have revealed that the Warburg effect promotes the radioresistance of various malignant tumors, including laryngeal carcinoma. Among the regulators involved in the Warburg effect, hexokinase-II (HK-II) is a crucial glycolytic enzyme that catalyzes the first essential step of glucose metabolism. HK-II is reportedly highly expressed in some human solid carcinomas by many studies. But for laryngeal carcinoma, there is only one. Till now, no studies have directly targeted inhibited HK-II and enhanced the radiosensitivity of laryngeal carcinoma. Accumulating evidence has shown that dysregulated signaling pathways often result in HK-II overexpression. Here, we summarize recent advances in understanding the association among the Warburg effect, HK-II, and the radioresistance of laryngeal carcinoma. We speculate on the feasibility of enhancing radiosensitivity by targeted inhibiting HK-II signaling pathways in laryngeal carcinoma, which may provide a novel anticancer therapy.
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Radioresistance remains a major obstacle for the radiotherapy treatment of cancer. Previous studies have demonstrated that the radioresistance of cancer is due to the existence of intrinsic cancer stem cells (CSCs), which represent a small, but radioresistant cell subpopulation that exist in heterogeneous tumors. By contrast, non-stem cancer cells are considered to be radiosensitive and thus, easy to kill. However, recent studies have revealed that under conditions of radiation-induced stress, theoretically radiosensitive non-stem cancer cells may undergo dedifferentiation subsequently obtaining the phenotypes and functions of CSCs, including high resistance to radiotherapy, which indicates that radiation may directly result in the generation of novel CSCs from non-stem cancer cells. These findings suggest that in addition to intrinsic CSCs, non-stem cancer cells may also contribute to the relapse and metastasis of cancer following transformation into CSCs. This review aims to investigate the radiation-induced generation of CSCs, its association with epithelial-mesenchymal transition and its significance with regard to the radioresistance of cancer.
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// Lei Chang 1,2 , Peter Graham 1,2 , Jingli Hao 1,2 , Jie Ni 1,2 , Junli Deng 1,2 , Joseph Bucci 1,2 , David Malouf 3 , David Gillatt 3,4 and Yong Li 1,2 1 Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia 2 St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia 3 Department of Urology, St George Hospital, Kogarah, NSW, Australia 4 Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia Correspondence to: Yong Li, email: // Keywords : cancer, radiotherapy, radioresistance, CSC, signaling pathway Received : October 13, 2015 Accepted : December 22, 2015 Published : December 24, 2015 Abstract Radiation therapy (RT) is one of the most important strategies in cancer treatment. Radioresistance (the failure to RT) results in locoregional recurrence and metastasis. Therefore, it is critically important to investigate the mechanisms leading to cancer radioresistance to overcome this problem and increase patients' survival. Currently, the majority of the radioresistance-associated researches have focused on preclinical studies. Although the exact mechanisms of cancer radioresistance have not been fully uncovered, accumulating evidence supports that cancer stem cells (CSCs) and different signaling pathways play important roles in regulating radiation response and radioresistance. Therefore, targeting CSCs or signaling pathway proteins may hold promise for developing novel combination modalities and overcoming radioresistance. The present review focuses on the key evidence of CSC markers and several important signaling pathways in cancer radioresistance and explores innovative approaches for future radiation treatment.
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RNF6 is verified to promote the malignant growth of colorectal cancer (CRC) and its level is linked to prognosis in CRC patients. Radioresistance is a key factor influencing prognosis in CRC. This study aimed to uncover the potential regulation of ring finger protein 6 (RNF6) in CRC radioresistance.RNF6 levels in radioresistant and non-radioresistant CRC patients were detected. In vitro and in vivo regulatory effects of RNF6 on radioresistant CRC cell lines and nude mice bearing radioresistant CRC were examined, respectively. The involvement of Wnt pathway in CRC radioresistance was explored by Western blot.RNF6 was highly expressed in radioresistant CRC species than that of non-radioresistant ones. Identically, RNF6 was upregulated in radioresistant CRC cells compared to parental cells. SW1116 cells overexpressing RNF6 were more tolerant to radiotherapy, and similar results were obtained in nude mice bearing radioresistant CRC with overexpression of RNF6. Moreover, the Wnt pathway was activated during RNF6-induced radioresistance improvement in CRC.RNF6 enhances radioresistance of CRC through activating the Wnt pathway.
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