NFAT/SIRT3 mediated regulation of metabolic adaptation driving prostate cancer bone metastasis
In this prostate cancer-focused project, we propose that prostate cancer cells adapt to the environmental stresses in the bone milieu in a non-conventional way and gain the capacity to convert nutrition to energy and basic cellular building blocks, namely, metabolic adaptation.
We hypothesize that this process is double-regulated by the hyper-activation of organ-specific, oncogenic NFAT (nuclear factor of activated T cells) signaling in combination with the suppression of metabolic repressor Sirtuin 3 (SIRT3).
Our early work disclosed an unexpected role for SIRT3 in the regulation of NFAT levels. Additionally, our studies, for the first time, have identified a collaborative and mutually interfering regulatory cascade as a critical mechanism that supports the metabolic adaptation and metastatic progression of prostate cancer cells in bone metastasis, thereby allowing cancer cells to survive amidst a limited nutrition supply and environmental stresses in the bone milieu.
The involvement of the indicated genes was supported by public genomics data and pilot biological studies. These findings provide a compelling rationale to investigate and target the indicated metabolic axis for bone metastases.