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Role of GDF15 in methylseleninic acid-mediated inhibition of cell proliferation and induction of apoptosis in prostate cancer cells.

ABSTRACT: The growth inhibitory efficacy of methylseleninic acid (MSA) in prostate cancer cells has been documented extensively. However, our understanding of the immediate targets that are key to the growth inhibitory effects of MSA remains limited. Here, using multiple preclinical prostate cancer models, we demonstrated in vitro and in vivo that GDF15 is a most highly induced, immediate target of MSA. We further showed that knockdown of GDF15 mitigates MSA inhibition of cell proliferation and induction of apoptosis. Analysis of gene expression data from over 1000 primary and 200 metastatic prostate cancer samples revealed that GDF15 expression is decreased in metastatic prostate cancers compared to primary tumors and that lower GDF15 levels in primary tumors are associated with higher Gleason scores and shorter survival of the patients. Additionally, pathways that are negatively correlated with GDF15 levels in clinical samples are also negatively correlated with MSA treatment in cultured cells. Since most, if not all, of these pathways have been implicated in prostate cancer progression, suppressing their activities by inducing GDF15 is consistent with the anticancer effects of MSA in prostate cancer. Overall, this study provides support for GDF15 as an immediate target of MSA in prostate cancer cells.

SUBMITTER: Zhang W

PROVIDER: S-EPMC6754141 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Role of GDF15 in methylseleninic acid-mediated inhibition of cell proliferation and induction of apoptosis in prostate cancer cells.

Zhang Wenbo W Hu Cheng C Wang Xiaojie X Bai Shanshan S Cao Subing S Kobelski Margaret M Lambert James R JR Gu Jingkai J Zhan Yang Y

PloS one 20190920 9

The growth inhibitory efficacy of methylseleninic acid (MSA) in prostate cancer cells has been documented extensively. However, our understanding of the immediate targets that are key to the growth inhibitory effects of MSA remains limited. Here, using multiple preclinical prostate cancer models, we demonstrated in vitro and in vivo that GDF15 is a most highly induced, immediate target of MSA. We further showed that knockdown of GDF15 mitigates MSA inhibition of cell proliferation and induction ...[more]

PMID: 31539407

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Project description:We have previously shown that carbon nanofibers (CNFs) and carbon nanotubes (CNTs) can sensitize prostate cancer (PCa) cells to platinum-based chemotherapeutics. In order to further verify this concept and to avoid a bias, the present study investigates the chemosensitizing potential of CNFs and CNTs to the conventional chemotherapeutics docetaxel (DTX) and mitomycin C (MMC), which have different molecular structures and mechanisms of action than platinum-based chemotherapeutics. DU-145 PCa cells were treated with DTX and MMC alone or in combination with the carbon nanomaterials. The impact of the monotreatments and the combinatory treatments on cellular function was then systematically analyzed by using different experimental approaches (viability, short-term and long-term proliferation, cell death rate). DTX and MMC alone reduced the viability of PCa cells to 94% and 68%, respectively, whereas a combined treatment with CNFs led to less than 30% remaining viable cells. Up to 17- and 7-fold higher DTX and MMC concentrations were needed in order to evoke a similar inhibition of viability as mediated by the combinatory treatments. In contrast, the dose of platinum-based chemotherapeutics could only be reduced by up to 3-fold by combination with carbon nanomaterials. Furthermore, combinatory treatments with CNFs led mostly to an additive inhibition of short- and long-term proliferation compared to the individual treatments. Also, higher cell death rates were observed in combinatory treatments than in monotreatments, e.g., a combination of MMC and CNFs more than doubled the cell death rate mediated by apoptosis. Combinations with CNTs showed a similar, but less pronounced impact on cellular functions. In summary, carbon nanomaterials in combination with DTX and MMC evoked additive to partly synergistic anti-tumor effects. CNFs and CNTs possess the ability to sensitize cancer cells to a wide range of structurally diverse chemotherapeutics and thus represent an interesting option for the development of multimodal cancer therapies. Co-administration of chemotherapeutics with carbon nanomaterials could result in a reduction of the chemotherapeutic dosage and thus limit systemic side effects.

Dataset Information

Role of GDF15 in methylseleninic acid-mediated inhibition of cell proliferation and induction of apoptosis in prostate cancer cells.

Publications

Role of GDF15 in methylseleninic acid-mediated inhibition of cell proliferation and induction of apoptosis in prostate cancer cells.

Similar Datasets

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