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PA28?/? Promote Breast Cancer Cell Invasion and Metastasis via Down-Regulation of CDK15.

ABSTRACT: PA28?/? activated immunoproteasome frequently participates in MHC class I antigen processing, however, whether it is involved in breast tumor progression remains largely unclear. Here, our evidences show that PA28?/? proteins are responsible for breast cancer cell migration, invasion, and metastasis. Knockdown of immunoproteasome core subunit ?5i also robustly suppresses the tumor cell migration and invasion. Interestingly, silencing of PA28?/? and ?5i up-regulates the protein expression of cyclin-dependent kinase 15 (CDK15). Our data further indicate that the loss of CDK15 is important for breast tumor cell invasion and metastasis. Taken together, this study implicates that targeting of PA28?/? represents a potential way for treatment of metastatic breast cancer.

SUBMITTER: Li S

PROVIDER: S-EPMC6883405 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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PA28α/β Promote Breast Cancer Cell Invasion and Metastasis via Down-Regulation of CDK15.

Li Shengnan S Dai Xiaoqin X Gong Kunxiang K Song Kai K Tai Fang F Shi Jian J

Frontiers in oncology 20191122

PA28α/β activated immunoproteasome frequently participates in MHC class I antigen processing, however, whether it is involved in breast tumor progression remains largely unclear. Here, our evidences show that PA28α/β proteins are responsible for breast cancer cell migration, invasion, and metastasis. Knockdown of immunoproteasome core subunit β5i also robustly suppresses the tumor cell migration and invasion. Interestingly, silencing of PA28α/β and β5i up-regulates the protein expression of cycl ...[more]

PMID: 31824858

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Project description:IntroductionT-cell lymphoma invasion and metastasis-inducing protein (Tiam1) is a Ras-related C3 botulinum toxin substrate (Rac)-specific guanine nucleotide exchange factor that was isolated based on its ability to induce a metastatic phenotype. In polarized migrating keratinocytes, Tiam1 is found at the leading edge where it cooperates with the Protease-activated receptor 1 (Par1) complex to establish front-rear polarity. Although a positive correlation has been observed between Tiam1 expression and tumor grade in a variety of human malignancies, including breast, its role in breast cancer cells has not yet been examined.MethodsTiam1 expression and Rac activity were examined in a panel of human breast cancer cell lines which exhibit different degrees of cell motility. The contribution of Tiam1 to cell motility was directly examined using transwell motility, and wound healing assays.ResultsAlthough we observe a striking, positive correlation between Tiam1 expression and cell motility in the panel of breast cancer cell lines, we do not observe a correlation between Tiam1 expression and overall levels of Rac activity. Consistent with this, small interfering ribonucleic acid (siRNA)-mediated suppression of Tiam1 expression limits the motility of cell lines in which Tiam1 expression is high (MDA-MB-231 and MDA-MB-453), but does not substantially alter the overall levels of activated Rac. Tiam1 overexpression is also not sufficient to increase the motility of more poorly motile cells (T-47D) or increase Rac activity. Immunofluorescence and cellular fractionations indicate that Tiam1 is found predominantly in the Golgi of breast cancer cells, and in the latter case Tiam1 was shown to co-fractionate with a limited pool of Rac1. Consistent with this Golgi localization, Tiam1 supports cell motility and Golgi reorientation in response to serum in a wound healing assay using MDA-MB-231and MDA-MB-435S cells.ConclusionsTiam1 expression correlates with cell motility in human breast cancer cells, and is required to support the motile phenotype. Localization of endogenous Tiam1 to the Golgi, and its demonstrated role in Golgi reorientation, suggest that it may support motility through a mechanism that is discrete from its known function in leading edge dynamics.

Dataset Information

PA28?/? Promote Breast Cancer Cell Invasion and Metastasis via Down-Regulation of CDK15.

Publications

PA28α/β Promote Breast Cancer Cell Invasion and Metastasis via Down-Regulation of CDK15.

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