Connexin 43 confers chemoresistance through activating PI3K

Pridham, Kevin J.; Shah, Farah; Sheng, Kevin L.; Guo, Sujuan; Liu, Min; Kanabur, Pratik; Lamouille, Samy; Lewis, Gabrielle; Morales, Marc; Jourdan, Jane; Grek, Christina L.; Ghatnekar, Gautam G; Varghese, Robin; Kelly, Deborah F.; Gourdie, Robert G.; Sheng, Zhi

doi:10.1101/2020.10.14.339275

Cited by 2 publications

(3 citation statements)

References 56 publications

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“…Moreover, aCT1 selectively inactivates phosphoinositide 3-kinase catalytic subunit b (PIK3CB, also called PI3Kb or p110b) in temozolomideresistant GSCs [9] and a combination of aCT1 and temozolomide obstructs the self-renewal and tumorigenicity of GSCs [10]. In line with the results of TAT-Cx43 266À283 in GSCs described above [4,5], Cx43-CT is vital to GSCs.…”

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confidence: 70%

“…In line with the results of TAT-Cx43 266À283 in GSCs described above [4,5], Cx43-CT is vital to GSCs. Because JM2 and aCT1 exhibit negligible toxicity to normal neural stem cells, same as TAT-Cx43 266À283 [8][9][10], targeting Cx43-CT represents a powerful and feasible therapeutic approach for selectively eliminating GSCs. Among these Cx43-CT mimetic peptides, only TAT-Cx43 266À283 targets metabolic plasticity in GSCs, making this peptide even more important in the development of effective therapeutics to slow down or prevent GBM progression associated with dormant and resilient GSCs.…”

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confidence: 99%

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Connexin 43 peptidic medicine for glioblastoma stem cells

Sheng

2021

EBioMedicine

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The role of connexin 43 (Cx43) in glioblastoma (GBM) is perplexing, making it difficult to develop Cx43-based therapies to treat this deadly brain cancer. For instance, Cx43 has long been considered as a tumor suppressor in glioma, because Cx43, as a gap junction (GJ) protein, forms membrane channels to enhance cell-cell communication, which suppresses the formation of glioma [1]. Indeed, reduced GJ intercellular communication (GJIC) is a hallmark of cancer [2]. However, recent researchÀthat highlights the importance of Cx43 in intertumoral and intratumoral heterogeneity in GBMÀhas challenged this model. A side population of GBM cells, called GBM stem cells (GSCs), has displayed considerably different traits compared to other GBM cells, one of which is the unusually strong ability to propagate a tumor in mice [3]. This helps explain why GBM patients often succumb to a progressive and recurrent disease because GSCs, spared by surgical resection, radiation, and chemotherapy, can grow another tumor in the brain. Eliminating GSCs is therefore an appealing therapeutic approach; however, targeting GSCs is challenging given their idiosyncratic nature that makes GSCs metabolically resilient compared to differentiated tumor cells and endows GSCs survival advantages particularly under unfavorable growth conditions. Recent research from Pelaz and her colleagues has provided possible answers to this challenge and offered a new therapeutic opportunity that allows us to eliminate dormant and resilient GSCs [4].This research stems from the finding from the Tabernero laboratory that Cx43's carboxyl terminus (CT), located inside of cells, activates SRC proto-oncogene, non-receptor tyrosine kinase (c-SRC) in patient-derived GSCs [5]. The activation of c-SRC subsequently promotes the motility, growth, and tumorigenicity of GSCs in vitro and in vivo [6]. Given that c-SRC plays a vital role in regulating metabolism in cancer, Pelaz et al., tested the hypothesis that Cx43-CT regulates GSCs' metabolic activity [4]. By treating GSCs with

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confidence: 70%

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confidence: 99%

Connexin 43 peptidic medicine for glioblastoma stem cells

Sheng

2021

EBioMedicine

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“…Supporting this, the pan-PI3K inhibitor, PX-866, has been found to block TMZ-induced autophagy, whilst promoting GBM cell death (103). In addition, the activation of PTEN/PI3K/AKT signaling has been reported to be an essential step in the development of TMZ resistance in GBM cells in a MGMT-dependent manner (104)(105)(106).…”

Section: Oncogenic Lncrnas Promote Tmz Resistance In Gliomasmentioning

confidence: 89%

Regulation of temozolomide resistance via lncRNAs: Clinical and biological properties of lncRNAs in gliomas (Review)

Sui

Xie

et al. 2022

Int J Oncol

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Gliomas are a primary types of intracranial malignancies and are characterized by a poor prognosis due to aggressive recurrence profiles. Temozolomide (TMZ) is an auxiliary alkylating agent that is extensively used in conjunction with surgical resection and forms the mainstay of clinical treatment strategies for gliomas. However, the frequent occurrence of TMZ resistance in clinical practice limits its therapeutic efficacy. Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) can play key and varied roles in glioma progression. lncRNAs have been reported to inhibit glioma progression by targeting various signaling pathways. In addition, the differential expression of lncRNAs has also been found to mediate the resistance of glioma to several chemotherapeutic agents, particularly to TMZ. The present review article therefore summarizes the findings of previous studies in an aim to report the significance and function of lncRNAs in regulating the chemoresistance of gliomas. The present review may provide further insight into the clinical treatment of gliomas. Contents 1. Introduction 2. Prominent role of lncRNAs in glioma 3. Oncogenic lncRNAs promote TMZ resistance in gliomas 4. Tumor suppressive lncRNAs influence the sensitivity of gliomas to TMZ 5. Conclusions and future perspectives

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Connexin 43 confers chemoresistance through activating PI3K

Cited by 2 publications

References 56 publications

Connexin 43 peptidic medicine for glioblastoma stem cells

Connexin 43 peptidic medicine for glioblastoma stem cells

Regulation of temozolomide resistance via lncRNAs: Clinical and biological properties of lncRNAs in gliomas (Review)

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