Connexin 43 confers chemoresistance through activating PI3K

Pridham, Kevin J.; Shah, Farah; Hutchings, Kasen R.; 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:10.1038/s41389-022-00378-7

Cited by 16 publications

(29 citation statements)

References 77 publications

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“…Cx43 is a component of gap junctions that are responsible in part for intercellular communication. Recent studies have indicated that Cx43 controls the response of GBM cells to TMZ through various mechanisms, such as modulating mitochondrial apoptosis, and activating P13K signaling (Gielen et al, 2013; Munoz et al, 2014; Pridham et al, 2022). Pridham et al (2022) have shown that expression of Cx43 protein in high‐grade glioma is higher than other connexins.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have indicated that Cx43 controls the response of GBM cells to TMZ through various mechanisms, such as modulating mitochondrial apoptosis, and activating P13K signaling (Gielen et al, 2013; Munoz et al, 2014; Pridham et al, 2022). Pridham et al (2022) have shown that expression of Cx43 protein in high‐grade glioma is higher than other connexins. They also show that high levels of Cx43 messenger RNA were associated with poor prognosis of GBM patients (Pridham et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, there was also a significant decrease of viability in the αCT1 = 100 μM, TMZ = 0 condition, again indicating that αCT1 also induces other cellular changes in some subsets of GBM cells. mechanisms, such as modulating mitochondrial apoptosis, and activating P13K signaling (Gielen et al, 2013;Munoz et al, 2014;Pridham et al, 2022). Pridham et al (2022) have shown that expression of Cx43 protein in high-grade glioma is higher than other connexins.…”

Section: Validation Of αCt1-tmz Treatment In Patient-derived Gbm Orga...mentioning

confidence: 99%

See 2 more Smart Citations

αCT1 peptide sensitizes glioma cells to temozolomide in a glioblastoma organoid platform

Che

DePalma

Sivakumar

et al. 2023

Biotech & Bioengineering

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Glioblastoma (GBM) is the most common form of brain cancer. Even with aggressive treatment, tumor recurrence is almost universal and patient prognosis is poor because many GBM cell subpopulations, especially the mesenchymal and glioma stem cell populations, are resistant to temozolomide (TMZ), the most commonly used chemotherapeutic in GBM. For this reason, there is an urgent need for the development of new therapies that can more effectively treat GBM. Several recent studies have indicated that high expression of connexin 43 (Cx43) in GBM is associated with poor patient outcomes. It has been hypothesized that inhibition of the Cx43 hemichannels could prevent TMZ efflux and sensitize otherwise resistance cells to the treatment. In this study, we use a three-dimensional organoid model of GBM to demonstrate that combinatorial treatment with TMZ and αCT1, a Cx43 mimetic peptide, significantly improves treatment efficacy in certain populations of GBM. Confocal imaging was used to visualize changes in Cx43 expression in response to combinatorial treatment. These results indicate that Cx43 inhibition should be pursued further as an improved treatment for GBM.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Validation Of αCt1-tmz Treatment In Patient-derived Gbm Orga...mentioning

confidence: 99%

See 1 more Smart Citation

αCT1 peptide sensitizes glioma cells to temozolomide in a glioblastoma organoid platform

Che

DePalma

Sivakumar

et al. 2023

Biotech & Bioengineering

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“…For example, PI3K/AKT leads to direct phosphorylation of multiple glycolysis enzymes to promote glucose utilization, but can also activate alternative pathways in the absence of glucose [ 249 , 250 , 251 ]. Connexins have been implicated within these signal transduction pathways, including many aspects related to cancer cell function such as motility, invasion, proliferation and therapy resistance [ 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 ]. Ongoing studies drawing connections between these growth promoting pathways and their effects on connexins, will undoubtedly continue to converge on metabolic involvement.…”

Section: Emerging Connectionsmentioning

confidence: 99%

Connexins and Glucose Metabolism in Cancer

Jones

Bodenstine

2022

IJMS

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Connexins are a family of transmembrane proteins that regulate diverse cellular functions. Originally characterized for their ability to mediate direct intercellular communication through the formation of highly regulated membrane channels, their functions have been extended to the exchange of molecules with the extracellular environment, and the ability to modulate numerous channel-independent effects on processes such as motility and survival. Notably, connexins have been implicated in cancer biology for their context-dependent roles that can both promote or suppress cancer cell function. Moreover, connexins are able to mediate many aspects of cellular metabolism including the intercellular coupling of nutrients and signaling molecules. During cancer progression, changes to substrate utilization occur to support energy production and biomass accumulation. This results in metabolic plasticity that promotes cell survival and proliferation, and can impact therapeutic resistance. Significant progress has been made in our understanding of connexin and cancer biology, however, delineating the roles these multi-faceted proteins play in metabolic adaptation of cancer cells is just beginning. Glucose represents a major carbon substrate for energy production, nucleotide synthesis, carbohydrate modifications and generation of biosynthetic intermediates. While cancer cells often exhibit a dependence on glycolytic metabolism for survival, cellular reprogramming of metabolic pathways is common when blood perfusion is limited in growing tumors. These metabolic changes drive aggressive phenotypes through the acquisition of functional traits. Connections between glucose metabolism and connexin function in cancer cells and the surrounding stroma are now apparent, however much remains to be discovered regarding these relationships. This review discusses the existing evidence in this area and highlights directions for continued investigation.

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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 - 106 ).…”

Section: Oncogenic Lncrnas Promote Tmz Resistance In Gliomasmentioning

confidence: 99%

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 16 publications

References 77 publications

αCT1 peptide sensitizes glioma cells to temozolomide in a glioblastoma organoid platform

αCT1 peptide sensitizes glioma cells to temozolomide in a glioblastoma organoid platform

Connexins and Glucose Metabolism in Cancer

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

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