Activation of Ras signaling pathways by pyrroloquinoline quinone in NIH3T3 mouse fibroblasts

Abstract

Abstract. Pyrroloquinoline quinone (PQQ) has been implicated in certain physiological activities in mammals such as functioning as a potent growth factor in mice, and promoting DNA synthesis in human fibroblasts. These are clearly important physiological functions, however, the molecular mechanisms involved in PQQ activity are not yet fully understood. In order to address this, in this study we analyzed the effects of PQQ on the proliferation of NIH3T3 mouse fibroblasts and on their intracellular signal transduction mechanism. When activated c-Ha-ras-transformed NIH3T3 cells were treated with PQQ in the presence of 0.5% calf serum in DMEM, the cells showed significantly increased viability. After PQQ addition, flow cytometric analysis revealed a decrease in the population of cells in the G 0 /G 1 phase and a concomitant increase in cells in the S and G 2 /M phases. Although treatment with SNAP, an NO donor, reduced cell viability, this effect was abolished by the addition of PQQ. Activation of ERK and PKC-ε was detected immediately after the addition of PQQ, and subsequent increases in the phosphorylation of Rb and c-Jun were observed. On the other hand, protein expression levels of growth-inhibitory molecules such as IκB and p27 decreased after PQQ treatment. These results suggest that PQQ stimulates cell proliferation through NO-sensitive Rasmediated signaling pathways.

Pyrroloquinoline quinone rescues hippocampal neurons from glutamate-induced cell death through activation of Nrf2 and up-regulation of antioxidant genes

“…PQQ has been reported to display a strong anti-apoptotic activity in cortical neurons and to activate multiple cell survival pathways that are essential to cell growth, survival and differentiation, such as Ras/ERK and PI3K/Akt signaling (Kumazawa et al, 2007;Mebratu and Tesfaigzi, 2009;Zhang et al, 2011). As is known, the down-regulation of GSK3β activity is one of the mechanisms involved in cell survival, promoting the function of PI3K/Akt signaling pathway (Pap and Cooper, 1998).…”

Protein kinase C as a stress sensor

“…Because nitric oxide (NO) was found to reduce cell viability in PQQ treated cells, this pathway is considered to be NO sensitive. Again, the role of PKCε in PQQ mediated cell growth is unknown [20]. A pro-inflammatory agent lipopolysaccharide (LPS) that induces astrocyte stellation has enhanced activity in the presence of PKCε.…”

Influence of Adding Pyrroloquinoline Quinone to Parenteral Nutrition on Gut‐Associated Lymphoid Tissue

“…This substance, initially identified as a coenzyme necessary for certain oxidation-reduction reactions and cell signaling pathways, has recently become of interest as a potentially critical coenzyme in mammals. [14][15][16][17][18][25][26][27][28][29] The importance of PQQ in mammalian health has been reported based on its omission from chemically defined diets, resulting in a wide range of systemic responses, including growth impairment, compromised immune responsiveness, and abnormal reproductive performance in mouse and rat experimental models. 11-13-13,17,18 In the immune system, PQQ deficiency is associated with a reduction in interleukin (IL)-2 level and decreased Tand B-cell sensitivity to mitogens 12 .…”