An ether derivative of tocotrienol (T3), 6-O-carboxypropyl-α-tocotrienol (T3E) is more stable and has more strong anticancer activity compared to T3. Although T3E has shown it's a drastic cytotoxic effect against malignant mesothelioma (MM) cells within pharmacologic dose, the exact mechanism by which T3E functions as an antimesothelioma agent has not been completely clarified. In this study, we estimated signal molecules responsible for the antimesothelioma effect of T3E by cascade analysis on gene expression. As a result, 49 proteins were detected as possible signal molecules which were related to the antimesothelioma effect of T3E. Of the proteins, interleukin-4 receptor (IL-4R) was determined as a key molecule which was closely related to the antimesothelioma effect, because IL-4R has not been known as the signal molecule which is related to antimesothelioma effect of T3E in previous studies. Conventional pathway analysis showed suppression of IL-4 signaling by down-regulation of IL-4R when treated with T3E. On the contrary, pathway analysis showed activation of IL-1 and IL-6 signaling. Taken together, this study suggests that IL-4 signaling is important for survival of MM, and that T3E may act as an effective antimesothelioma agent due to the inhibition of IL-4 signaling.