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Small interfering RNA targeting HMGN5 induces apoptosis via modulation of a mitochondrial pathway and Bcl-2 family proteins in prostate cancer cells.

ABSTRACT: We investigated the importance of HMGN5, a nuclear protein that binds to nucleosomes, unfolds chromatin, and affects transcription, in the LNCaP prostate cancer cell line. We also examined the molecular mechanisms that promote apoptosis of LNCaP cells after infection with small interfering RNA (siRNA) targeting HMGN5 (siRNA-HMGN5). The androgen-dependent LNCaP human prostate cancer cells were infected with siRNA-HMGN5. Apoptosis was detected using the Annexin V-PE/7-AAD double staining and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assays. Mitochondrial membrane potential was measured by JC-1 staining. HMGN5 and GAPDH mRNA expression were determined using real-time PCR. Bcl-2 and other apoptosis-related protein levels were determined by Western blot analysis. Caspase activity was measured by cleavage of the caspase substrate. Infection with siRNA targeting HMGN5 efficiently and specifically reduced the HMGN5 expression in LNCaP cells. The downregulation of HMGN5 induced remarkable apoptosis of LNCaP cells and resulted in the reduction of mitochondrial membrane potential. The induction of cell apoptosis was accompanied by the upregulation of Bax, the Bax/Bcl-2 ratio and the activation of caspase3. The HMGN5-targeted siRNA was effective in downregulating the expression of HMGN5 in androgen-dependent prostate cancer cells and inducing cell apoptosis via the regulation of a caspase-related mitochondrial pathway and Bcl-2 family proteins. This study suggests that HMGN5 may be a potential molecular target with therapeutic relevance for the treatment of prostate cancer.

SUBMITTER: Zhang XY

PROVIDER: S-EPMC3720167 | biostudies-other | 2012 May

REPOSITORIES: biostudies-other

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Project description:Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acute myeloid leukemia (AML); however, complete responses are observed in only 20% of patients, suggesting that targeting BCL-2 alone is insufficient to yield durable responses. Here, we assessed the efficacy of coadministration of the PI3K/mTOR inhibitor GDC-0980 or the p110?-sparing PI3K inhibitor taselisib with the selective BCL-2 antagonist venetoclax in AML cells. Tetracycline-inducible downregulation of BCL-2 significantly sensitized MV4-11 and MOLM-13 AML cells to PI3K inhibition. Venetoclax/GDC-0980 coadministration induced rapid and pronounced BAX mitochondrial translocation, cytochrome c release, and apoptosis in various AML cell lines in association with AKT/mTOR inactivation and MCL-1 downregulation; ectopic expression of MCL-1 significantly protected cells from this regimen. Combined treatment was also effective against primary AML blasts from 17 patients, including those bearing various genetic abnormalities. Venetoclax/GDC-0980 markedly induced apoptosis in primitive CD34+/38-/123+ AML cell populations but not in normal hematopoietic progenitor CD34+ cells. The regimen was also active against AML cells displaying intrinsic or acquired venetoclax resistance or tumor microenvironment-associated resistance. Either combinatorial treatment markedly reduced AML growth and prolonged survival in a systemic AML xenograft mouse model and diminished AML growth in two patient-derived xenograft models. Venetoclax/GDC-0980 activity was partially diminished in BAK-/- cells and failed to induce apoptosis in BAX-/- and BAX-/-BAK-/- cells, whereas BIM-/- cells were fully sensitive. Similar results were observed with venetoclax alone in in vitro and in vivo systemic xenograft models. Collectively, these studies demonstrate that venetoclax/GDC-0980 exhibits potent anti-AML activity primarily through BAX and, to a lesser extent, BAK. These findings argue that dual BCL-2 and PI3K inhibition warrants further evaluation in AML.Significance: Combined treatment with clinically relevant PI3K and BCL-2 inhibitors may prove effective in the treatment of acute myeloid leukemia. Cancer Res; 78(11); 3075-86. ©2018 AACR.

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Small interfering RNA targeting HMGN5 induces apoptosis via modulation of a mitochondrial pathway and Bcl-2 family proteins in prostate cancer cells.

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