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Reduced IQGAP2 expression promotes EMT and inhibits apoptosis by modulating the MEK-ERK and p38 signaling in breast cancer irrespective of ER status.

ABSTRACT: IQGAP2, a member of the IQGAP family, functions as a tumor suppressor in most of the cancers. Unlike IQGAP1 and IQGAP3, which function as oncogenes in breast cancer, the role of IQGAP2 is still unexplored. Here we report a reduced expression of IQGAP2, which was associated with lymph node positivity, lymphovascular invasion, and higher age in breast cancer patients. We found an inverse correlation of IQGAP2 expression levels with oncogenic properties of breast cancer cell lines in estrogen receptor (ER) independent manner. IQGAP2 expression enhanced apoptosis via reactive oxygen species (ROS)-P38-p53 pathway and reduced epithelial-mesenchymal transition (EMT) in a MEK-ERK-dependent manner. IQGAP2-IQGAP1 ratio correlated negatively with phospho-ERK levels in breast cancer patients. Pull-down assay showed interaction of IQGAP1 and IQGAP2. IQGAP2 overexpression rescued, IQGAP1-mediated ERK activation, suggesting the possibility of IQGAP1 sequestration by IQGAP2. IQGAP2 depletion, in a tumor xenograft model, increased tumor volume, tumor weight, and phospho-ERK expression. Overall, our findings suggest that IQGAP2 is negatively associated with proliferative and metastatic abilities of breast cancer cells. Suppression of IQGAP1-mediated ERK activation is a possible route via which IQGAP2 restricts oncogenic properties of breast cancer cells. Our study highlights the candidature of IQGAP2 as a potent target for therapeutic intervention.

SUBMITTER: Kumar D

PROVIDER: S-EPMC8041781 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Utilizing the Citrobacter rodentium-induced transmissible murine colonic hyperplasia (TMCH) model, we measured hyperplasia and NF-?B activation during progression (days 6 and 12 post-infection) and regression (days 20-34 post-infection) phases of TMCH. NF-?B activity increased at progression in conjunction with bacterial attachment and translocation to the colonic crypts and decreased 40% by day 20. NF-?B activity at days 27 and 34, however, remained 2-3-fold higher than uninfected control. Expression of the downstream target gene CXCL-1/KC in the crypts correlated with NF-?B activation kinetics. Phosphorylation of cellular I?B? kinase (IKK)?/? (Ser(176/180)) was elevated during progression and regression of TMCH. Phosphorylation (Ser(32/36)) and degradation of I?B?, however, contributed to NF-?B activation only from days 6 to 20 but not at later time points. Phosphorylation of MEK1/2 (Ser(217/221)), ERK1/2 (Thr(202)/Tyr(204)), and p38 (Thr(180)/Tyr(182)) paralleled IKK?/? kinetics at days 6 and 12 without declining with regressing hyperplasia. siRNAs to MEK, ERK, and p38 significantly blocked NF-?B activity in vitro, whereas MEK1/2-inhibitor (PD98059) also blocked increases in MEK1/2, ERK1/2, and IKK?/? thereby inhibiting NF-?B activity in vivo. Cellular and nuclear levels of Ser(536)-phosphorylated (p65(536)) and Lys(310)-acetylated p65 subunit accompanied functional NF-?B activation during TMCH. RSK-1 phosphorylation at Thr(359)/Ser(363) in cellular/nuclear extracts and co-immunoprecipitation with cellular p65-NF-?B overlapped with p65(536) kinetics. Dietary pectin (6%) blocked NF-?B activity by blocking increases in p65 abundance and nuclear translocation thereby down-regulating CXCL-1/KC expression in the crypts. Thus, NF-?B activation persisted despite the lack of bacterial attachment to colonic mucosa beyond peak hyperplasia. The MEK/ERK/p38 pathway therefore seems to modulate sustained activation of NF-?B in colonic crypts in response to C. rodentium infection.

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Reduced IQGAP2 expression promotes EMT and inhibits apoptosis by modulating the MEK-ERK and p38 signaling in breast cancer irrespective of ER status.

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