Selective IκBβ mediated NFκB Activation is Required for the Propagation of Mitochondria‐to‐Nucleus Stress Signaling and Tumor Invasiveness

Partial depletion of mitochondrial DNA (mtDNA) or treatment with mitochondrial ionophore, CCCP activate mitochondria‐to‐nucleus stress signaling (MNSS). MNSS induces elevation of cytosolic calcium, activation of calcium dependent factors, protein kinasess, as well as calcineurin (Cn), a protein phosphatase. MNSS also induced activation of a novel NFκB pathway (cRel:p50) through Cn dependent dephosphorylation of IκBβ. The stress signaling induced the expression of specific nuclear gene targets, including calcium channel receptor RyR1, and the tumor promoting genes cathepsinL and TGFβ1. MNSS induced invasive phenotypes in C2C12 myocytes in otherwise non invasive cells, which was inhibited by Cn inhibitor FK506. In the present study we further investigated the role of Cn mediated inactivation of IκBβ pathway in the propagation of MNSS and formation of invasive phenotypes by Si RNA mediated knock down of IκBβ (Si IκBβ). Our results show a reversal of MNSS as seen by reduced translocation of NFκB proteins (cRel and p50) to the nucleus. Also there was a reversal of cathL and RyR1 gene expression patterns and steady state protein levels in Si IκBβ cells but not Si IkBa cells. Furthermore in vitro matrigel invasion assay showed a remarkable decrease in the level of invasive property in the SiIκBβ cells suggesting a direct link between the IκBβ mediated MNSS and induction of invasive phenotype. Therefore this study suggests that IκBβ can be used as an important molecular target in invasive tumor cells with induced MNSS. Supported by NIH Grant CA‐22762