Methylation profiles reveal distinct subgroup of hepatocellular carcinoma patients with poor prognosis

10.1371/journal.pone.0104158PLoS ONE98e10415

Erratum: Methylation profiles reveal distinct subgroup of hepatocellular carcinoma patients with poor prognosis (PLoS ONE (2014) 9:8 (e104158) (DOI:10.1371/journal.pone.0104158))

10.1371/journal.pone.0146690PLoS ONE111e014669

Cryopreservation of cancer-initiating cells derived from glioblastoma

Frontiers in Bioscience - Scholar3 S2698-70

ST3GAL1-Associated Transcriptomic Program in Glioblastoma Tumor Growth, Invasion, and Prognosis

10.1093/jnci/djv326Journal of the National Cancer Institute1082djv32

A distinct reactive oxygen species profile confers chemoresistance in glioma-propagating cells and associates with patient survival outcome

10.1089/ars.2012.4999Antioxidants and Redox Signaling19182261-2279ARSI

Dual modulation of MCL-1 and mTOR determines the response to sunitinib

Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib. Furthermore, higher doses of sunitinib were cytotoxic, triggered a decline in MCL-1 levels, and inhibited mTORC1 signaling. Mechanistically, we determined that sunitinib modulates MCL-1 stability by affecting its proteasomal degradation. Dual modulation of MCL-1 stability at different dose ranges of sunitinib was due to differential effects on ERK and GSK3\u3b2 activity, and the latter also accounted for dual modulation of mTORC1 activity. Finally, comparison of patient samples prior to and following sunitinib treatment suggested that increases in MCL-1 levels and mTORC1 activity correlate with resistance to sunitinib in patients