Rac1 protects epithelial cells against anoikis

Rho family members play a critical role in malignant transformation. Anchor age-independent growth and the ability to avoid apoptosis caused by loss of anchorage (anoikis) are important features of transformed cells. Here we s how that constitutive activation of Rac1 inhibits anoikis in Madin-Darby ca nine kidney (MDCK) epithelial cells. Constitutively active Rac1-V12 decreas es DNA fragmentation and caspase activity by 50% in MDCK cells kept in susp ension. In addition, expression of Rac1-V12 in MDCK cells in suspension con ditions causes an increase in the number of surviving cells. We also invest igated the signaling pathways that are activated by Rac1 to stimulate cell survival. We show that expression of Rac1-V12 in MDCK cells in suspension s timulates a number of signaling cascades that have been implicated in the c ontrol of cell survival, including the p42/44 ERK, p38, protein kinase B, a nd nuclear factor kappaB pathways. Using specific chemical or protein inhib itors of these respective pathways, we show that Rac1-mediated cell surviva l strongly depends on phosphatidylinositol 3-kinase activity and that activ ation of ERK, p38, and NF-kappaB are largely dispensable for Rac1 survival signaling. In conclusion, these studies demonstrate that Rac1 can suppress apoptosis in epithelial cells in anchorage-independent conditions and sugge st a potential role for Rac1-mediated survival signaling in cell transforma tion.