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Cytotoxic activity of HTI-286 in prostate cancer

ABSTRACT: HTI-286, an analogue of hemiasterlin, interferes with microtubule dynamics and circumvents transport-based resistance to taxanes. In this study we evaluate the inhibitory effects of HTI-286 on human prostate cancer growth in vitro and in different in vivo models. The results show that HTI-286 is a potent inhibitor of proliferation and induced marked increases in apoptotic rates in all cell lines tested. Despite similar transcriptomic changes regarding cell death and cell cycle-regulating genes after exposure to HTI-286 or docetaxel, the gene array revealed distinct molecular signatures for both compounds. Keywords: Drug comparison

ORGANISM(S): Homo sapiens

PROVIDER: GSE8325 | GEO | 2007/06/29

SECONDARY ACCESSION(S): PRJNA101313

REPOSITORIES: GEO

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Project description:Diaphanous-related formin-3 (DIAPH3), a cytoskeletal regulator of the formin family, is lost at high frequency in metastatic breast and prostate cancers and has characteristics of a non-canonical metastasis suppressor. We previously demonstrated that DIAPH3 silencing evokes transition to an “amoeboid” phenotype, characterized by rapid motility, RhoA/ROCK and MEK/ERK pathway activation, dynamic membrane blebbing, and increased shedding of microvesicles. Here we report that low DIAPH3 mRNA expression correlates with reduced survival in multiple cancer patient cohorts. In line with induction of amoeboid behavior, traction force microscopy (TFM) revealed that polarized force generation, contractility, and response to substrate stiffness are reduced by DIAPH3 loss. Proteomic analyses revealed that DIAPH3 precipitates with tubulins, and reciprocal co-immunoprecipitation analyses revealed greater binding of DIAPH3 to MT polymers than soluble tubulin. DIAPH3 also bound to acetylated-tubulin (Ac-tubulin), suggesting association with a stable MT population. DIAPH3 silencing reduced Ac-tubulin and increased the cellular content of dynamic MT, as indicated by TFM and live cell imaging. DIAPH3 silencing also increased responsiveness to MT-disrupting agents. Treatment with the taxanes paclitaxel and docetaxel, and the non-taxane epothilone B, induced a greater change in Ac-tubulin when cells lacked DIAPH3. Intracellular accumulation of Oregon Green 488-paclitaxel was also increased by DIAPH3 loss, and accordingly, DIAPH3 silencing enhanced cytotoxicity by paclitaxel, docetaxel, or epothilone B. Gene expression profiles of breast cancer patients treated with chemotherapeutic regimens containing taxanes revealed an association of low DIAPH3 expression with improved relapse-free survival. Collectively, these results suggest that regulation of MT stability/dynamics by DIAPH3 enhances amoeboid tumor cell susceptibility to microtubule poisons. These findings have potential therapeutic implications.

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Cytotoxic activity of HTI-286 in prostate cancer

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