PP2A Level in Colorectal Cancer Cells Predicts the Response of p38 Targeted Therapy

The p38 mitogen-activated protein kinases (MAPK) play an imporp38i-stimulated group, SB202190 enhanced ERK/RSK-mediated TSC2 tant role in the regulation of cell proliferation and survival, in response to various environmental cues, e.g., oxidative stress and inflammatory cytokines (Cuenda and Rousseau, 2007). p38 MAPK activity is elevated in types of cancer, including colorectal cancer (CRC) (Gupta et al., 2014), and accordingly, several p38 inhibitors (p38is) have been in early clinical trials. However, surprisingly, none of the p38is has shown positive effects on CRC. This remains mysterious. In this issue of EBioMedicine, Zhang et al. (2015), for the first time, reported opposite responses of two subgroups of CRC cells to p38is. In the first subgroup (including RKO, CACO2 and SW480), named p38iinhibited group, p38 inhibitor (p38i) SB202190 inhibited cell proliferation and induced apoptosis; while in the second subgroup (including HCT116, SW1116 and SW620), designated p38i-stimulated group, SB202190 increased cell proliferation and survival. Similar results were observed in LY2228820 and BIRB796, two other p38is. The findings were verified in CRC xenografts in mice, indicating that there exist two subgroups of CRC cells, which respond to p38is differentially. Interestingly, Zhang et al. (2015) also foundopposing effects of p38is on mTORC1 in the two subgroups of CRC cells, correlating with the effects on cell growth. Since SB202190 inhibits mTORC1 through MAPKactivated protein kinase 2 (MK2)-dependent phosphorylation of TSC2 (S1254) (Li et al., 2003), and MK2 is directly regulated by p38 MAPK (Cuenda and Rousseau, 2007). Zhang et al. (2015) hypothesized that the opposite effects of p38is on mTORC1 in the CRC cells link to the status of TSC1/2 complex, a negative regulator of mTORC1 (Inoki et al., 2002). The results support their hypothesis, as silencing TSC1 or TSC2 abrogated the negative or positive effects of SB202190 on mTORC1 and cell growth. TSC2 can be phosphorylated byAkt at T1462, p38/MK2 at S1254, and ERK–RSK at S664/S1798 (Inoki et al., 2002; Li et al., 2003; Roux et al., 2004; Ma et al., 2005). Zhang et al. (2015) also found that TSC2 phosphorylation differed between the two subgroups of CRC cells, in response to p38i. In the p38i-inhibited group, SB202190 suppressed p38/MK2-mediated TSC2 phosphorylation (S1254), causing activation of TSC1/2 and thereby inhibition of mTORC1, but had no effects on Akt/ERK–RSK-mediated TSC2 phosphorylations. In contrast, in the