We found that inhibition of S1P generation or function with SK1-II or SphK1 knockdown suppressed the enhanced invasion of cancer cells induced by DR5 knockdown, blocked DR5 knockdown-induced activation of ERK1/2 and JNK/AP-1 signaling including elevation of TRAF2 and MMP1, and attenuated DR5 knockdown-induced TRAF2 polyubiquitination (Figs. 3 and 4). Here, MMP1 is linked to cancer.