Cancer cell death induced by the NAD antimetabolite Vacor discloses the antitumor potential of SARM1

In a previous study, we showed that the NAD antimetabolite Vacor is metabolized by two enzymes implicated in the NAD salvage pathway—to Vacor mononucleotide (VMN) by nicotinamide phosphoribosyltransferase (NAMPT) and, in turn, to Vacor adenine dinucleotide (VAD) by nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2)—leading to NAD depletion and antitumor activity. Recent findings in neurons show that VMN activates SARM1, a NAD glycohydrolase, triggering NAD depletion and degeneration. In this study, we report that altering NMNAT2 levels did not affect Vacor-induced NAD depletion or cell death. In contrast, SARM1 expression alone was sufficient to induce Vacor sensitivity. Further, we report that cancer cells sense the abnormal expression of SARM1 and readily induce the expression of NMNAT2. Overall, the data underscore the antitumor potential of pharmacological approaches aimed at activating SARM1.