Manganese suppresses tumor growth through hyper-activating IRE1α

Abstract

IRE1 and its downstream XBP1 signal is the most conserved unfolded protein response pathway that cells utilize to combat endoplasmic reticulum stress, also known to be utilized by tumor cells to adapt to harsh environment, leading to tumor progression. Several inhibitors against IRE1 have been developed, some of which show promising effect in clinical trial for cancer therapy, but none of them have been used in practice. Considering that hyper-activation of IRE1 induces cell death, we hypothesize that activation of IRE1 could be an alternative way for tumor suppression. Here, we identified divalent manganese ion as a potent activator to IRE1, which interacts with the cytosolic part of IRE1 directly, augmenting the downstream pro-apoptotic pathway but not the pro-survival outcome. Mn2+ limits tumor growth in xenograft model in an IRE1-dependent way. Our finding suggests pharmacological activation of IRE1 as an underestimated but promising way in cancer therapy. HighlightsO_LIMn2+ binds to cytosolic segment of IRE1 and promotes its oligomerization C_LIO_LIMn2+ hyper-activates IRE1 and induces downstream terminal UPR under ER stress C_LIO_LIMn2+ does not elevate XBP1s expression C_LIO_LIMn2+ as an IRE1 activator impairs tumor growth in xenograft model C_LI