Sc-11 * Differential Connexin Function Enhances Self-Renewal in Glioblastoma

Hitomi, M.; Deleyrolle, Loic P.; Sinyuk, Maksim; Otvos, Balint; Brunet, Sylvain; Jarrar, Awad; Flavahan, William; Goan, W.; Mulkearns-Hubert, Erin E.; Zhang, A.; Rohaus, Mark R.; Oli, Monika W.; Vedam‐Mai, Vinata; Fortin, Jeff M.; Futch, Hunter S.; Wu, Qiulian; Ahluwalia, Manmeet; Rich, Jeffery B.; Lathia, Justin D.

doi:10.1093/neuonc/nou275.11

Cited by 1 publication

(2 citation statements)

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“…Low levels of Cx43 expression and formation of associated gap junctions have been observed in GSCs in previous studies 26,27 . Given the significant non-junctional roles of Cx43 associated with cancer progression, we sought to isolate the function of Cx43 in these GSCs that reportedly have few gap junctions.…”

Section: Introductionmentioning

confidence: 64%

“…Proliferating GSCs display a loss of Cx43-dependent gap junctions at the plasma membrane that is accompanied by reduced intercellular communication, and Cx43 has been shown to be expressed at much lower levels in GSCs compared to their differentiated counterparts 26,27 . Although we confirmed Cx43 expression is low in GSCs compared to differentiated GSCs, we demonstrate, for the first time, an enrichment of Cx43 non-junctional cytoplasmic localization at the microtubules in GSCs.…”

Section: Discussionmentioning

confidence: 99%

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Increased interaction between connexin43 and microtubules is critical for glioblastoma stem-like cell maintenance and tumorigenicity

Smyth,

Guo,

O’Rourke

et al. 2024

Preprint

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Glioblastoma (GBM) is the most common primary tumor of the central nervous system. One major challenge in GBM treatment is the resistance to chemotherapy and radiotherapy observed in subpopulations of cancer cells, including GBM stem-like cells (GSCs). These cells hold the ability to self-renew or differentiate following treatment, participating in tumor recurrence. The gap junction protein connexin43 (Cx43) has complex roles in oncogenesis and we have previously reported an association between Cx43 and GBM chemotherapy resistance. Here, we report, for the first time, increased direct interaction between non-junctional Cx43 with microtubules in the cytoplasm of GSCs. We hypothesize that non-junctional Cx43/microtubule complexing is critical for GSC maintenance and survival and sought to specifically disrupt this interaction while maintaining other Cx43 functions, such as gap junction formation. Using a Cx43 mimetic peptide of the carboxyl terminal tubulin-binding domain of Cx43 (JM2), we successfully ablated Cx43 interaction with microtubules in GSCs. Importantly, administration of JM2 significantly decreased GSC survival in vitro, and limited GSC-derived tumor growth in vivo. Together, these results identify JM2 as a novel peptide drug to ablate GSCs in GBM treatment.

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Section: Introductionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%