Abstract
BackgroundSphingosine kinase-1 (SphK1) is an oncogenic lipid kinase notably involved in response to anticancer therapies in prostate cancer. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. Here, we explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival.Methodology/Principal FindingsShort-term androgen removal induced a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that was not observed in the hormono-insensitive PC-3 cells. Supporting the critical role of SphK1 inhibition in the rapid effect of androgen depletion, its overexpression could impair the cell growth decrease. Similarly, the addition of dihydrotestosterone (DHT) to androgen-deprived LNCaP cells re-established cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 could markedly impede the effects of DHT. Conversely, long-term removal of androgen support in LNCaP and C4-2B cells resulted in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE)-like cell phenotype. Importantly, inhibition of the PI3K/Akt pathway—by negatively impacting SphK1 activity—could prevent NE differentiation in both cell models, an event that could be mimicked by SphK1 inhibitors. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SphK1 activity.Conclusions/SignificanceWe report the first evidence that androgen deprivation induces a differential effect on SphK1 activity in hormone-sensitive prostate cancer cell models. These results also suggest that SphK1 activation upon chronic androgen deprivation may serve as a compensatory mechanism allowing prostate cancer cells to survive in androgen-depleted environment, giving support to its inhibition as a potential therapeutic strategy to delay/prevent the transition to androgen-independent prostate cancer.
Highlights
Prostate cancer is the most frequent malignancy accounting for 25% of all newly diagnosed cancers in men and is the second leading cause of death from cancer [1]
While Sphingosine kinase-1 (SphK1) activity can be stimulated by a wide array of growth factors [26], we have previously shown in prostate cancer cell and animal models that anticancer treatments lead to its inhibition suggesting that SphK1 could act a sensor to anticancer therapies [35,36,37,38]
Androgen deprivation did not alter the growth of PC-3 hormono-refractory (HR) cells whose growth was only altered by serum starvation (Fig. 1C).When compared to fetal bovine serum (FBS) conditions, androgen depletion in LNCaP induced a notable decrease in SphK1 activity within the first 24 h (Fig. 1D, left panel)
Summary
Prostate cancer is the most frequent malignancy accounting for 25% of all newly diagnosed cancers in men and is the second leading cause of death from cancer [1]. Prostate cancer cell proliferation is regulated by androgens and androgen deprivation therapy (ADT) is the standard of care in the management of patients with advanced disease. ADT induces changes in prostate cancer biology promoting its progression to the androgenrefractory state or hormone-refractory prostate cancer (HRPC) phenotype, with an associated life expectancy of only 15 to 20 months. It is not clear how prostate cancer cells make the transition from androgen-dependent to androgen-independent status after ADT. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. We explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival
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