Abstract Bone metastatic prostate cancer (BMPC) remains the leading cause of mortality among prostate cancer patients due to its resistance to current therapeutics and its reliance on the osteogenic microenvironment. The atypical protein kinase C (aPKC) isoforms PKC-ι and PKC-ζ have emerged as pivotal regulators of prostate cancer progression, metastasis, and inflammatory signaling. In this study, we investigated the molecular effects of two selective small-molecule inhibitors, ICA-1S (targeting PKC-ι) and ζ-Stat (targeting PKC-ζ), in DU-145 and PC-3 prostate cancer cells, as well as their interactions with the human osteoblast line hFOB 1.19. Our results demonstrated that both inhibitors effectively suppressed phosphorylation and activity of PKC-ι/ζ and downstream effectors, including Stat3, NFκB, and JNK/c-Jun, leading to marked reductions in cell migration and survival. Cytokine array analysis revealed that ICA-1S and ζ-Stat treatment significantly downregulated pro-metastatic and pro-inflammatory cytokines, including IL-6, IL-8, and CXCL-1, while upregulating IL-18 and ICAM-1, indicating a shift toward apoptotic and pyroptotic signaling. Immunofluorescence confirmed a decreased nuclear localization of Stat3. At the same time, co-immunoprecipitation assays demonstrated a reduced interaction between 14-3-3 and PKC-ι/ζ, supporting the disruption of key scaffold assemblies required for metastatic signaling. Collectively, our findings suggest that dual aPKC inhibition attenuates critical oncogenic cascades and reprograms the osteogenic niche to suppress prostate cancer survival and colonization in bone. These results identify ICA-1S and ζ-Stat as promising lead compounds for precision targeting of aPKC-driven prostate cancer metastasis. Citation Format: Grazielly Teodoro, Wishrawana Sarathi Ratnayake, Luke Lajmi, Sloan Breedy, Aaron Todman, Shreejana Rimal, Mildred Acevedo-Duncan, . Targeted inhibition of atypical PKC isoforms PKC-ι and PKC-ζ by ICA-1S and ζ-Stat suppresses oncogenic signaling and cytokine-mediated bone metastasis in prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7151.
Teodoro et al. (Fri,) studied this question.