Despite the fundamental importance of proteasomal degradation in cells, little is known about whether and how the 26S proteasome itself is regulated in coordination with various physiological processes. Here we show that the proteasome is dynamically phosphorylated during cell cycle at Thr25 of the 19S subunit Rpt3. CRISPR/Cas9-mediated genome editing, RNA interference and biochemical studies demonstrate that blocking Rpt3-Thr25 phosphorylation markedly impairs proteasome activity and impedes cell proliferation. Through a kinome-wide screen, we have identified dual-specificity tyrosine-regulated kinase 2 (DYRK2) as the primary kinase that phosphorylates Rpt3-Thr25, leading to enhanced substrate translocation and degradation. Importantly, loss of the single phosphorylation of Rpt3-Thr25 or knockout of DYRK2 significantly inhibits tumor formation by proteasome-addicted human breast cancer cells in mice. These findings define an important mechanism for proteasome regulation and demonstrate the biological significance of proteasome phosphorylation in regulating cell proliferation and tumorigenesis.
SignificanceCurcumin is an ancient drug derived from turmeric and has been found to exhibit potent anticancer properties albeit through controversial mechanisms of action. Using a biochemical model, mouse cancer model, and cellular models, we show that curcumin is a highly potent and selective inhibitor of dual-specificity tyrosine-regulated kinase 2 (DYRK2), a positive regulator of the 26S proteasome. Curcumin perturbs 26S proteasome activity via DYRK2 inhibition in various cancer cells and in the mouse cancer model leading to impairment of cell proliferation and reduction of cancer burden in mice. This novel mechanism of action of curcumin opens up new avenues for potential preventative or therapeutic strategies in proteasome-addicted cancers like triple-negative breast cancer and multiple myeloma.
A size changeable polymer micelle system with a dual shell, which increases in size under acidic pH conditions and is altered to smaller micelles, triggered by intracellular glutathione (GSH), is successfully developed. It is capable of direct delivering anticancer drugs to the nucleus of multidrug resistance (MDR) tumor cells for highly effective combating of drug resistant breast cancer.
In the past decade, bacteria‐based cancer immunotherapy has attracted much attention in the academic circle due to its unique mechanism and abundant applications in triggering the host anti‐tumor immunity. One advantage of bacteria lies in their capability in targeting tumors and preferentially colonizing the core area of the tumor. Because bacteria are abundant in pathogen‐associated molecular patterns that can effectively activate the immune cells even in the tumor immunosuppressive microenvironment, they are capable of enhancing the specific immune recognition and elimination of tumor cells. More attractively, during the rapid development of synthetic biology, using gene technology to enable bacteria to be an efficient producer of immunotherapeutic agents has led to many creative immunotherapy paradigms. The combination of bacteria and nanomaterials also displays infinite imagination in the multifunctional endowment for cancer immunotherapy. The current progress report summarizes the recent advances in bacteria‐based cancer immunotherapy with specific foci on the applications of naive bacteria‐, engineered bacteria‐, and bacterial components‐based cancer immunotherapy, and at the same time discusses future directions in this field of research based on the present developments.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.