MINDIN Exerts Protumorigenic Actions on Primary Prostate Tumors via Downregulation of the Scaffold Protein NHERF-1

Simple Summary Prostate cancer is one of the leading causes of death among men worldwide. Advanced prostate cancer is an incurable disease whose mechanisms of action are still not fully understood. Secretion of the matrix protein MINDIN has been associated with prostate tumor development towards advanced prostate cancer. We aimed to study the mechanisms whereby MINDIN promotes prostate cancer progression. Evaluation of human and mouse prostate cancer samples showed increased MINDIN expression associated with decreased expression of the adaptor protein Na+/H+ exchanger regulatory factor 1 (NHERF-1). We found that NHERF-1 was downregulated by MINDIN in prostate cancer, causing an increase in tumor cell migration and proliferation. These observations point to NHERF-1 as a key modulator of MINDIN actions on prostate cancer progression and suggest that both proteins could be potential targets for the development of future prostate cancer therapies. Advanced prostate cancer preferential metastasis to bone is associated with osteomimicry. MINDIN is a secreted matrix protein upregulated in prostate tumors that overexpresses bone-related genes during prostate cancer progression. Na+/H+ exchanger regulatory factor (NHERF-1) is a scaffold protein that has been involved both in tumor regulation and osteogenesis. We hypothesize that NHERF-1 modulation is a mechanism used by MINDIN to promote prostate cancer progression. We analyzed the expression of NHERF-1 and MINDIN in human prostate samples and in a premetastatic prostate cancer mouse model, based on the implantation of prostate adenocarcinoma TRAMP-C1 (transgenic adenocarcinoma of the mouse prostate) cells in immunocompetent C57BL/6 mice. The relationship between NHERF-1 and MINDIN and their effects on cell proliferation, migration, survival and osteomimicry were evaluated. Upregulation of MINDIN and downregulation of NHERF-1 expression were observed both in human prostate cancer samples and in the TRAMP-C1 model. MINDIN silencing restored NHERF-1 expression to control levels in the mouse model. Stimulation with MINDIN reduced NHERF-1 expression and triggered its mobilization from the plasma membrane to the cytoplasm in TRAMP-C1 cells. MINDIN-dependent downregulation of NHERF-1 promoted tumor cell migration and proliferation without affecting osteomimicry and adhesion. We propose that MINDIN downregulates NHERF-1 expression leading to promotion of processes involved in prostate cancer progression.

Automated summary

Prostate cancer is a leading cause of death in men worldwide. A study found that the matrix protein MINDIN promotes prostate cancer progression by downregulating the adaptor protein NHERF-1, leading to increased tumor cell migration and proliferation. This suggests that targeting MINDIN and NHERF-1 could be potential strategies for future prostate cancer therapies.