Inauhzin(c)

Activation of the unfolded protein response (UPR), triggered by endoplasmic reticulum (ER) stress, upregulates molecular chaperones, such as glucose-regulated protein 78 kDa (GRP78), to promote cellular re-localization and oncogenic signaling. Previously, we demonstrated that nanoparticle encapsulation of INZ-C (n-INZ-C) inhibits cancer cell growth in vitro and in vivo with no toxicity to normal cells. Yet, it remains completely unknown why INZ-C is specifically toxic to cancer cells. In our attempt to address this question, we identified GRP78 as a new target of INZ-C. We showed that INZ-C specifically binds to GRP78 using a combination of proteomic, biophysical, and cell-based approaches. Since GRP78 has been previously shown to translocate to the cell surface in cancer cells, we sought to evaluate the role of GRP78 in the cellular uptake and bioactivity of n-INZ-C. Intriguingly, we found that GRP78 knockdown leads to a significant reduction in cellular uptake and increase in IC₅₀ concentration. Further investigation revealed nuclear translocation of GRP78 following n-INZ-C treatment in cancer cells, but not in normal cells. Taken together, these findings not only unveil GRP78 as a novel target of INZ-C, but also indicate binding to the deregulated cancer cell-surface protein as the possible molecular mechanism underlying cancer cell-specific toxicity of the small molecule. The study also strongly suggests the potential of n-INZ-C as a promising GRP78-targeted anti-cancer therapy and offers a new approach to improve current front-line treatments.