Receptor-interacting protein 3 (RIP3) is a serine/threonine protein kinase, which has extensive substrates including its cognate kinase RIP1 and multiple metabolic enzymes involving oxidative phosphorylation1, 2. RIP3 has been shown to be essential for development, immunity and some physiological or pathophysiological responses to exogenous and endogenous stimuli3, 4, 5. In 2009, three groups independently reported that RIP3 acted as a molecular switch between apoptosis and necrosis (also called as necroptosis) 6, 7, 8. Specifically, RIP3 could turn tumor necrosis factor (TNF)-induced cell death from apoptosis to necrosis6. Most of small-molecule anticancer drugs elicit their anticancer effects via apoptotic induction9. However, it is unclear whether RIP3 affects the cellular sensitivity to small-molecule anticancer drugs.

Both A cells and N cells were kindly gifted from Prof Jiahuai HAN, who used them to successfully demonstrate the role of RIP3 in regulating TNF-inducing cell death6. The differential sensitivity of the RIP3-deficient and proficient murine fibroblasts to the Top1 inhibitors suggests a role of RIP3 in determining the cellular sensitivity to those agents. In this case, however, RIP3 does not seem to directly affect the choice of cell death between apoptosis and necrosis, because no significant difference of the cellular sensitivity to the other examined anticancer drugs except camptothecins was detectable (data not shown) and because RIP3-based differential responses of A cells and N cells to the Top1 inhibitors took place actually at the levels of the target protein Top1 and DNA double-strand breaks, not only at the level of cell death. In contrast, our data seem to imply that RIP3 is involved in the DNA damage induced by the Top1 inhibitors and/or subsequent repair. As a clinically important class of anticancer drugs, Top1 inhibitors are extensively used to treat various solid tumors such as colon and lung cancers. Occurrence of drug resistance to those inhibitors is a serious obstacle to successful therapy in the clinic11. The differential sensitivity of A cells and N cells to SN38 and chimmitecan also suggests that RIP3 could contribute to cellular resistance to Top1 inhibitors. Actually, we detected and found that RIP3 was expressed at high levels in cancer cells originated from different human tissues including blood (K562), liver (SMMC-7402 and SMMC-7721), colon (HCT116), stomach (MKN45), lung (A549), breast (MDA-MB-468, MDA-MB-231, T47D, and BT549), cervix (HeLa) and bone (Rh30) (data not shown). Inhibition of RIP3 might be an alternative approach to circumventing drug resistance. However, the exact molecular mechanisms remain to be further clarified.

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