Cancer cells manage to divide in the context of gross chromosomal abnormalities. These abnormalities can promote bypass of normal restraints on cell proliferation but at a cost of mitotic vulnerabilities that can be attacked by chemotherapy. Determining how cancer cells balance these issues may permit chemotherapeutic sensitivity to be leveraged more efficiently. From a pan-genomic small interfering RNA screen for modifiers of chemoresponsiveness, we identified the tumor antigen acrosin binding protein (ACRBP)/OY-TES-1 as a specifier of paclitaxel resistance. ACRBP expression is normally restricted to the testes but is detected in a wide variety of cancers, including most ovarian cancers. We found that ACRBP is both necessary and sufficient for paclitaxel resistance in ovarian cancer cell lines and ovarian tumor explants. Moreover, high ACRBP expression correlated with reduced survival time and faster relapse among ovarian cancer patients. We identified the mitotic spindle protein NuMA as an ACRBP-interacting protein that could account for the effects of ACRBP on paclitaxel sensitivity. In cancer cells, ACRBP restricted a NuMA-dependent abrogation of a mitotic spindle assembly that is otherwise pathologic. As a consequence, ACRBP depletion resulted in mitotic errors and reduced proliferative fitness that could be rescued by NuMA codepletion. We propose that the codependent relationship of ACRBP and NuMA in cancer cells reflects their passage through a selection bottleneck during tumor evolution, one which requires the acquisition of traits that normalize mitotic perturbations that orig-
In the fetal sheep, parturition is triggered by an increase in the activity of the fetal hypothalamus‐ pituitary‐adrenal (HPA) axis which, in turn, augments the biosynthesis of oestrogen by the placenta. Parturition can be prevented or delayed by destruction of the paraventricular nucleus (PVN), pituitary or adrenal, or stimulated by infusions of adrenocorticotropin (ACTH) or glucocorticoids. We have previously reported that physiological increases in fetal plasma concentrations of oestradiol have a neuroendocrine effect to increase both basal and hypotension‐stimulated ACTH secretion. The present study was performed to test the effect of oestradiol on the central baroreceptor and chemoreceptor reflex pathways. We used immunohistological techniques to identify various neuroanatomical regions which are activated by hypotension and, subsequently, those areas modified by oestrogen's action and baroreceptor and chemoreceptor denervation. We assessed cellular activation in these brain regions by immunostaining for Fos, the protein product of c‐fos, an immediate early response gene. We found that oestradiol increased Fos abundance in nucleus tractus solitarius (NTS), rostral ventrolateral medulla (RVLM), and PVN, and augmented the increase in Fos in these regions in response to a 10 min period of brachiocephalic arterial occlusion (BCO). Carotid sinus denervation blocked the Fos response to BCO, but not to oestrogen alone, in these regions. In contrast, the hippocampus responded to BCO with increase Fos in intact fetuses, but did not respond to oestrogen treatment. None of the treatments altered Fos expression in cerebral cortex or in cerebellum. We conclude that oestradiol augments the activity of the central baroreceptor and chemoreceptor reflex pathways, and that it may influence fetal ACTH secretion via this site of action.
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