Tumour cells can employ extracellular Ins(1,2,3,4,5,6)P₆ and multiple inositol-polyphosphate phosphatase 1 (MINPP1) dephosphorylation to improve their proliferation

InsP₆ [Ins(1,2,3,4,5,6)P₆; phytate] is the most abundant inositol phosphate in mammalian cells with cytosolic/nuclear concentrations of up to 50 μM. We noticed that InsP₆ in culture medium at a concentration of ≤50 μM significantly stimulates H1299 tumour cell growth, whereas larger concentrations of InsP₆ inhibit growth. A detailed study of the fate of 30 μM InsP₆ added to H199 cells revealed a major fraction of InsP₆ initially precipitates as cell-surface metal complexes, but becomes slowly re-solubilized by extracellular dephosphorylation first to InsP₃ isomers and subsequently to free myo-inositol. The precipitated metal-InsP₆ complex is endocytosed in a receptor-independent but intact-glycocalyx-dependent manner and appears in lysosomes, where it is immediately dephosphorylated to Ins(1,2,4,5,6)P₅ and very slowly to free inositol. By RNA knockdown, we identified secreted and lysosome targeted MINPP1 (multiple inositol-polyphosphate phosphatase 1), the mammalian 3-phytase, to be essentially involved both in extracellular and in lysosomal InsP₆ dephosphorylation. The results of the present study indicate that tumour cells employ this enzyme to utilize the micronutrients myo-inositol and metal-phosphate when encountering extracellular InsP₆ and thus to enhance their growth potential.