Microcystin-LR promotes cell proliferation in the mice liver by activating Akt and p38/ERK/JNK cascades

Microcystin-LR (MC-LR), a heptapeptide produced by blue-green algae, is shown to induce cytotoxicity by inhibiting protein phosphatase 2A (PP2A) activity. Our previous study revealed that MC-LR promoted cell proliferation in vitro by activating the Akt/mTORC1/S6K1 pathway. This study aims to further investigate the effects of MC-LR on cell proliferation and the correlated mechanisms in vivo. Mice were injected intraperitoneally with 20-80 μg/kg/d MC-LR from 2 h (hours) to 4 d (days). The results showed that the associations of MC-LR with PP2A/C (PP2A C subunit) were concentration-dependent but not time-dependent in the liver, whereas the total PP2A activity was inhibited in both concentration and time dependent manners. The PP2A regulator α4 was found to release its associated PP2A/C as MC-LR bound to PP2A/C. Importantly, 80 μg/kg MC-LR promoted liver cell proliferation beginning at 1 d post exposure, and hyperproliferation also occurred in the 40 μg/kg group at 4 d after exposure. Meanwhile, the Akt/mTORC1/S6K1 and Akt/β-catenin signaling pathways were activated as early as at 2 h post exposure. Furthermore, MC-LR also activated ERK/p38/JNK MAPKs as early as at 2 h post exposure, which was supported by the hyperphosphorylation of their substrates, ATF-2, c-Jun and c-Myc. Interestingly, the total c-Jun and c-Myc levels also increased after MC-LR exposure. These findings indicate that MC-LR can also promote cell proliferation in vivo, and the activation of Akt and MAPK signaling pathways due to PP2A inhibition is proposed to participate in this process.