Mechanism of induction of cell differentiation and cell death by inhibitors against V-ATPase

本课题研究了V-ATP酶抑制剂如巴非霉素、灵菌菌素和去甲氧苷抑制细胞生长、诱导细胞分化和诱导细胞凋亡的机制，以及它们抑制质子转运的机制，发现去甲氧苷-B和-E均抑制溶酶体质子泵，而只有destruxin-E能诱导PC 12细胞突起生长，(2)灵菌红素由于其H ^+ /Cl同向转运活性而解除了各种质子泵活性，（3）灵菌红素，如巴弗洛霉素A，诱导神经突向外生长（NOG），（4）灵菌红素诱导的NOG，如巴弗洛霉素诱导的NOG，需要从头合成新的信使RNA以及蛋白质合成，对MAP激酶，丝氨酸/苏氨酸磷酸酶，tambjamine类抗生素BE-18591也具有H ^+ /CU协同转运体的作用，能抑制猪胃质子泵，抑制胃壁细胞分泌 *cid，抑制破骨细胞分化，抑制免疫淋巴细胞增殖，并诱导NOG和细胞凋亡，这表明这些H ^+ /C1共转运体表现出的多种生物活性可能是由于它们的H ^+ /C1共转运活性。然而，四吡咯，另一个H ^+ /CV同向转运体，不诱导NOG。从这些结果中，我们得出结论，V-ATP酶抑制剂对细胞内pH的影响并不参与这些化合物所显示的各种生物活性（包括诱导NOG）。

In this research project, we have studied the machanism of (1) inhibition of cell growth, (2) induction of cell differentiation, and (3) induction of apoptosis, by V-ATPase inhibitors like bafilomycins, prodigiosins and destruxins, as well as the mechanims of inhibition of proton translocation by these inhibitors.We found (1) that both destrauxin-B and -E inhibited lysosomal proton pump, but only destruxin-E induced induced neurite out growth (NOG) of PC12 cells., (2) that prodigisins uncoupled various proton pump activities due to their H ^+ /Cl symport activity, (3) that prodigiosins, like bafilomycin A ^<1'> induced neurite out growth (NOG), and (4) that the prodigiosin-induced NOG, like bafolomycin-induced one, required de novo synthesis of new messenger RNA as well as protein synthesis, was sensitive to the inhibitors of MAP kinases, serine/threonine phosphatases, tyr-kinases, tyr-phosphatases, calmidulin and phospholipase A ^<2' > but resistant to inhibitors of trk tyrosine kinase and protein kinase A.BE-18591, a tambjamine group antibiotics, also behaved as H ^+ /CU symporters and inhibited hog gastric proton pump, inhibit *cid secretion by gastric parietal cells, inhibited osteoclast differentiation, suppressed proliferation of immune lymphocytes, and induced both NOG and apoptosis, suggesting that the variety of biological activities displayed by these H ^+ /C1 symporters may be due to their H ^+ /C1 symport activity. However, tetrapyrrole, another H ^+ /CV symporter, did not induced NOG.From these results, we conclud that the effect of V-ATPase inhibitors on the intracellular pH does not participate in the variety of biological activities (including induction of NOG) displayed by these compounds.