p38α limits the contribution of MAP17 to cancer progression in breast tumors

Abstract

MAP17 is a small, 17-kDa, non-glycosylated membrane protein that is overexpressed in a percentage of carcinomas. In the present work, we have analyzed the role of MAP17 expression during mammary cancer progression. We have found that MAP17 is expressed in 60% human mammary tumors while it is not expressed in normal or benign neoplasias. MAP17 levels increased with breast tumor stage and were strongly correlated with mammary tumoral progression. A significant increase in the levels of reactive oxygen species (ROS) was observed in MAP17-expressing cells, as compared with parental cells. This increase was further paralleled by an increase in the tumorigenic capacity of carcinoma cells but not in immortal non-tumoral breast epithelial cells, which provides a selective advantage once tumorigenesis has begun. Expression of specific MAP17 shRNA in proteinexpressing tumor cells reduced their tumorigenic capabilities, which suggests that this effect is dependent upon MAP17 protein expression. Our data show that ROS functions as a second messenger that enhances tumoral properties, which are inhibited in non-tumoral cells. We have found that p38a activation mediates this response. MAP17 triggers a ROS-dependent, senescence-like response that is abolished in the absence of p38a activation. Furthermore, in human breast tumors, MAP17 activation is correlated with a lack of phosphorylation of p38a. Therefore, MAP17 is overexpressed in late-stage breast tumors, in which oncogenic activity relies on p38 insensitivity to induce intracellular ROS.

MAP17 and the double-edged sword of ROS

“…Therefore, overexpression of MAP17 protects Rat1a fibroblasts from Mycinduced apoptosis through ROS-mediated activation of the PI3K/AKT signaling pathway [36]. However, the increased tumoral properties of carcinoma cells were not paralleled in naïve non-tumoral cells [57], indicating that MAP17 provides a selective advantage once tumorigenesis has begun. Our data demonstrate that ROS act as a second messenger that enhances tumoral properties but only in those cells where the senescence/apoptotic signal provided by ROS is uncoupled.…”

“…A mild increase in ROS has been shown to activate signaling cascades which can seriously influence the regulation of cell growth and tumorigenic processes [4,10,11,16,31,42,43,57,110]. However, a further increase in ROS levels raises oxidative stress and creates a potentially toxic environment for the cell.…”

“…The relevance of MAP17 as a general marker for the malignant stages of human tumors still needs to be confirmed in additional tumor types and larger cohorts. Furthermore, MAP17 expression seems to correlate with AKT473 phosphorylation and p38 T180/Y182 dephosphorylation [57].…”

“…The increased malignant cell behavior induced by MAP17 is associated with an increase in ROS production, and the treatment of MAP17-expressing cells with antioxidants results in a reduction in the tumorigenic properties of these cells. The MAP17-dependent increase in ROS and tumorigenesis is dependent on its PDZ-binding domain because disruption of this sequence by point mutations abolishes the ability of MAP17 to enhance ROS production and tumorigenesis [57,59].…”

“…Furthermore, in human breast tumors, MAP17 activation is correlated with lack of p38a phosphorylation. Therefore, MAP17 is overexpressed in late-stage breast tumors, in which oncogenic activity relies on p38 insensitivity to induced intracellular ROS [57].…”