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STAT3 Stabilizes IKK? Protein through Direct Interaction in Transformed and Cancerous Human Breast Epithelial Cells.

ABSTRACT: Signal transducer and activator of transcription 3 (STAT3) and nuclear factor-?B (NF-?B) are two representative transcription factors that play a critical role in inflammation-associated tumorigenesis through multi-level cooperation. Unlike other types of tumors, breast carcinomas have shown a significant dependency on the non-classical NF-?B pathway as well as the classical one. The ? subunit of the inhibitor of the ?B kinase (IKK) complex, IKK?, is involved in both classical and non-classical activation of NF-?B. Although the cross-talk between STAT3 and NF-?B has been suggested in several studies, the interplay between STAT3 and the regulators of NF-?B including IKK? has not been fully clarified yet. In this study, we observed overexpression and co-localization of IKK? and STAT3 in human breast cancer tissues as well as in H-Ras transformed human breast epithelial (H-Ras MCF-10A) and breast cancer (MDA-MB-231) cells. By utilizing small interfering RNA (siRNA) technology, we were able to demonstrate that STAT3 up-regulated IKK?, but not IKK? or IKK?, in these cells. This was attributable to direct binding to and subsequent stabilization of IKK? protein by blocking the ubiquitin-proteasome system. Notably, we identified the lysine 44 residue of IKK? as a putative binding site for STAT3. Moreover, siRNA knockdown of IKK? attenuated viability, anchorage-independent growth and migratory capabilities of H-Ras MCF-10A cells. Taken together, these findings propose a novel mechanism responsible for NF-?B activation by STAT3 through stabilization of IKK?, which contributes to breast cancer promotion and progression. Thus, breaking the STAT3-IKK? alliance can be an alternative therapeutic strategy for the treatment of breast cancer.

SUBMITTER: Hahn YI

PROVIDER: S-EPMC7795115 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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STAT3 Stabilizes IKKα Protein through Direct Interaction in Transformed and Cancerous Human Breast Epithelial Cells.

Hahn Young-Il YI Saeidi Soma S Kim Su-Jung SJ Park Se-Young SY Song Na-Young NY Zheng Jie J Kim Do-Hee DH Lee Han-Byoel HB Han Wonshik W Noh Dong-Young DY Na Hye-Kyung HK Surh Young-Joon YJ

Cancers 20201230 1

Signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) are two representative transcription factors that play a critical role in inflammation-associated tumorigenesis through multi-level cooperation. Unlike other types of tumors, breast carcinomas have shown a significant dependency on the non-classical NF-κB pathway as well as the classical one. The α subunit of the inhibitor of the κB kinase (IKK) complex, IKKα, is involved in both classical and non-classical ...[more]

PMID: 33396715

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Project description:BackgroundRecent research has yielded a wealth of data underscoring the key role of the cancer microenvironment, especially immune and stromal cells, in the progression of cancer and the development of metastases. However, the role of adjacent benign epithelial cells, which provide initial cell-cell contacts with cancer cells, in tumor progression has not been thoroughly examined. In this report we addressed the question whether benign MECs alter the transformed phenotype of human breast cancer cells.MethodsWe used both in vitro and in vivo co-cultivation approaches, whereby we mixed GFP-tagged MCF-10A cells (G2B-10A), as a model of benign mammary epithelial cells (MECs), and RFP-tagged MDA-MB-231-TIAS cells (R2-T1AS), as a model of breast cancer cells.ResultsThe in vitro studies showed that G2B-10A cells increase the colony formation of R2-T1AS cells in both soft agar and clonogenicity assays. Conditioned media derived from G2B-10A cells enhanced colony formation of R2-T1AS cells, whereas prior paraformaldehyde (PFA) fixation of G2B-10A cells abrogated this enhancement effect. Moreover, two other models of benign MECs, MCF-12A and HuMECs, also enhanced R2-T1AS colony growth in soft agar and clonogenicity assays. These data reveal that factors secreted by benign MECs are responsible for the observed enhancement of the R2-T1AS transformed phenotype. To determine whether G2B-10A cells enhance the tumorigenic growth of co-injected R2-T1AS cells in vivo, we used the nude mouse xenograft assay. Co-injecting R2-T1AS cells with G2B-10A cells +/- PFA-fixation, revealed that G2B-10A cells promoted a ~3-fold increase in tumor growth, irrespective of PFA pre-treatment. These results indicate that soluble factors secreted by G2B-10A cells play a less important role in promoting R2-T1AS tumorigenesis in vivo, and that additional components are operative in the nude mouse xenograft assay. Finally, using array analysis, we found that both live and PFA-fixed G2B-10A cells induced R2-T1AS cells to secrete specific cytokines (IL-6 and GM-CSF), suggesting that cell-cell contact activates R2-T1AS cells.ConclusionsTaken together, these data shift our understanding of adjacent benign epithelial cells in the cancer process, from passive, noncontributory cells to an active and tumor-promoting vicinal cell population that may have significant effects early, when benign cells outnumber malignant cells.

Dataset Information

STAT3 Stabilizes IKK? Protein through Direct Interaction in Transformed and Cancerous Human Breast Epithelial Cells.

Publications

STAT3 Stabilizes IKKα Protein through Direct Interaction in Transformed and Cancerous Human Breast Epithelial Cells.

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