gsk1210151a and Neoplasm-Metastasis

Ovarian cancer (OC) is a common malignant tumor with a high probability of metastasis. Thus, it is urgently necessary to develop new drugs that inhibit tumor metastasis. Bromodomain and extraterminal (BET) inhibitors targeting bromodomain-containing proteins are currently recognized as novel anticancer agents. Herein, we explored the effects of i-BET151, a BET bromodomain inhibitor, on OC metastasis and on antitumor immunity. Our experiments showed that i-BET151 decreased the viability and induced apoptosis, senescence, and cell cycle arrest of cancer cells. In addition, phosphorylated-Stat3 (Tyr705) amounts OC cell invasion and migration, and expression of matrix metalloproteinases (MMP-9 and MMP-2) decreased. Moreover, tumor metastasis in the abdomen of the OC model was inhibited by i-BET151. Notably, i-BET151-promoted immunogenic cell death (ICD) was confirmed in vivo; it was demonstrated with ICD markers. Furthermore, treatment with i-BET151 promoted infiltration by CD8

Topics: Animals; Apoptosis; Bcl-2-Like Protein 11; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Immunity; Mice, Inbred BALB C; Neoplasm Invasiveness; Neoplasm Metastasis; Ovarian Neoplasms; Up-Regulation

Recent studies suggest that BET inhibitors are effective anti-cancer therapeutics. Here we show that BET inhibitors are effective against murine primary mammary tumors, but not pulmonary metastases. BRD4, a target of BET inhibitors, encodes two isoforms with opposite effects on tumor progression. To gain insights into why BET inhibition was ineffective against metastases the pro-metastatic short isoform of BRD4 was characterized using mass spectrometry and cellular fractionation. Our data show that the pro-metastatic short isoform interacts with the LINC complex and the metastasis-associated proteins RRP1B and SIPA1 at the inner face of the nuclear membrane. Furthermore, histone binding arrays revealed that the short isoform has a broader acetylated histone binding pattern relative to the long isoform. These differential biochemical and nuclear localization properties revealed in our study provide novel insights into the opposing roles of BRD4 isoforms in metastatic breast cancer progression.

Topics: Animals; Apoptosis Regulatory Proteins; Cell Cycle Proteins; Cell Line, Tumor; Cell Nucleus; Chromosomal Proteins, Non-Histone; Disease Models, Animal; Female; GTPase-Activating Proteins; Heterocyclic Compounds, 4 or More Rings; Histones; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Mice; Microtubule-Associated Proteins; N-Terminal Acetyltransferase E; N-Terminal Acetyltransferases; Neoplasm Metastasis; Neoplasms; Nuclear Envelope; Nuclear Proteins; Protein Binding; Protein Isoforms; Protein Transport; Transcription Factors; Tumor Burden