Sulindac Sulfide Suppresses Oncogenic Transformation Through let-7b-Mediated Repression of K-Ras Signaling

Cell transformation is a key early event in tumorigenesis, yet the molecular mechanisms underlying its chemoprevention remain poorly defined. Here, we show that sulindac sulfide (SS), the active metabolite of the NSAID sulindac, inhibits chemically induced transformation of NIH/3T3 cells through a COX-independent mechanism. SS treatment upregulates the tumor-suppressive microRNA let-7b, which directly targets K-Ras and suppresses downstream ERK signaling. Notably, K-Ras negatively regulates let-7b via activation of ERK and LIN28B, forming a reciprocal feedback loop that drives transformation. SS disrupts this loop by downregulating p-ERK and LIN28B, thereby restoring let-7b expression. Functional analyses confirmed that let-7b, but not let-7g, is required for SS-mediated inhibition of transformation. In human colon cancer tissues and cell lines, let-7b is downregulated, but restored upon SS treatment. These findings identify a novel let-7b/K-Ras/LIN28B/ERK regulatory axis targeted by SS and provide mechanistic insight into its role in early-stage cancer chemoprevention.