TIAM1-RAC1 promote small-cell lung cancer cell survival through antagonizing Nur77-induced BCL2 conformational change
Authors
Payapilly, AishwaryaGuilbert, Ryan
Descamps, Tine
White, Gavin R M
Magee, Peter
Zhou, Cong
Kerr, Alastair
Simpson, Kathryn L
Blackhall, Fiona H
Dive, Caroline
Malliri, Angeliki
Affiliation
Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park SK10 4TGIssue Date
2021
Metadata
Show full item recordAbstract
Small-cell lung cancer (SCLC), an aggressive neuroendocrine malignancy, has limited treatment options beyond platinum-based chemotherapy, whereafter acquired resistance is rapid and common. By analyzing expression data from SCLC tumors, patient-derived models, and established cell lines, we show that the expression of TIAM1, an activator of the small GTPase RAC1, is associated with a neuroendocrine gene program. TIAM1 depletion or RAC1 inhibition reduces viability and tumorigenicity of SCLC cells by increasing apoptosis associated with conversion of BCL2 from its pro-survival to pro-apoptotic function via BH3 domain exposure. This conversion is dependent upon cytoplasmic translocation of Nur77, an orphan nuclear receptor. TIAM1 interacts with and sequesters Nur77 in SCLC cell nuclei and TIAM1 depletion or RAC1 inhibition promotes Nur77 translocation to the cytoplasm. Mutant TIAM1 with reduced Nur77 binding fails to suppress apoptosis triggered by TIAM1 depletion. In conclusion, TIAM1-RAC1 signaling promotes SCLC cell survival via Nur77 nuclear sequestration.Citation
Payapilly A, Guilbert R, Descamps T, White G, Magee P, Zhou C, et al. TIAM1-RAC1 promote small-cell lung cancer cell survival through antagonizing Nur77-induced BCL2 conformational change [Internet]. Vol. 37, Cell Reports. Elsevier BV; 2021. p. 109979.Journal
Cell ReportsDOI
10.1016/j.celrep.2021.109979PubMed ID
34758330Additional Links
https://dx.doi.org/10.1016/j.celrep.2021.109979Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1016/j.celrep.2021.109979
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