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Variations in calcium concentration within the endoplasmic reticulum ([Ca 2 + ] E R ) may play a role in cell growth. This study evaluates the regulation of calcium pools by growth modulators of prostate cancer (PC) cells, the insulin growth factor (IGF), and the tumor necrosis growth factor-alpha (TNFalpha) as well as evaluating the possible role of [Ca 2 + ] E R variations as signals for growth modulation. We show that IGF (5 ng/ml), which increases cell growth, induces an increase in [Ca 2 + ] E R whereas TNFalpha (1 ng/ml) which reduces cell proliferation and induces apoptosis, reduces [Ca 2 + ] E R . IGF-induced [Ca 2 + ] E R increase is correlated to an overexpression of the sarcoendoplasmic calcium-ATPase 2B (SERCA2b), whereas TNFalpha-induced [Ca 2 + ] E R decrease is associated to a reduction in SERCA2b expression. Pretreatment with epidermal growth factors (EGF) or IGF does not prevent TNFalpha from affecting the induction of apoptosis, [Ca 2 + ] E R reduction and SERCA2b downregulation. Reduction in [Ca 2 + ] E R induced by thapsigargin (TG) (from 1 pM to 1 μM, 48 h) reduces LNCaP growth in a dose dependent manner and induces apoptosis when cells are treated with 1 μM TG. We also show that a transient TG application (1 pM, 1 nM, 1 μM 15 min) is insufficient to induce a long lasting decrease in [Ca 2 + ] E R , since [Ca 2 + ] E R remains identical to the control for 48 h following TG application. These treatments (1 pM and 1 nM, 15 min) do not modify cell growth. However, TG (1 μM, 15 min) induces apoptosis. We thus identify [Ca 2 + ] E R and SERCA2b as a central targets for causing LNCaP PC cell life or death induced by growth modulators. Furthermore our results indicate that calcium pool contents can regulate cell growth.