Argyrin A Reveals a Critical Role for the Tumor Suppressor Protein p27kip1 in Mediating Antitumor Activities in Response to Proteasome Inhibition

Abstract

A reduction in the cellular levels of the cyclin kinase inhibitor p27(kip1) is frequently found in many human cancers and correlates directly with patient prognosis. In this work, we identify argyrin A, a cyclical peptide derived from the myxobacterium Archangium gephyra, as a potent antitumoral drug. All antitumoral activities of argyrin A depend on the prevention of p27(kip1) destruction, as loss of p27(kip1) expression confers resistance to this compound. We find that argyrin A exerts its effects through a potent inhibition of the proteasome. By comparing the cellular responses exerted by argyrin A with siRNA-mediated knockdown of proteasomal subunits, we find that the biological effects of proteasome inhibition per se depend on the expression of p27(kip1).

Activated cytotoxic lymphocytes promote tumor progression by increasing the ability of 3LL tumor cells to mediate MDSC chemoattraction via Fas signaling

“…17 MDSCs inhibit the activation and proliferation of T and natural killer cells, promote the metastasis of tumors, advance the cell cycle and increase the invasive capacity of tumors to mediate tumor escape. [17][18][19][20][21][22][23] A study of tumor patients over the course of clinical therapy revealed that there are large amounts of MDSCs in the peripheral blood and tumor-infiltrating tissues of patients suffering from head and neck cancers, squamous-cell epithelioma, mammary cancer and small-cell lung cancer. After tumor tissues are surgically removed, the number of MDSCs in the peripheral blood of tumor patients decreased.…”

Synthetic and structural studies on syringolin A and B reveal critical determinants of selectivity and potency of proteasome inhibition

“…Treatment with bortezomib, however, often causes severe side effects, probably as a consequence of its low selectivity or is hampered by bortezomib resistance (7). Consequently, new selective and bioavailable proteasome inhibitors are needed, and various screening programs have already been performed and led to the discovery of several diverse and potent natural product-based proteasome inhibitors (8)(9)(10)(11)(12)(13)(14).…”

Structural and Functional Characterization of the Immunoproteasome

“…Furthermore, CP inhibitors block proinflammatory signalling cascades such as NF-κB and the expression of anti-apoptotic target genes [41b] . Ultimately, tumour suppressor genes like the cyclin kinase inhibitor p27 kip1 [43] induce apoptosis in transformed cells, while healthy cells remain unaffected [41a] .…”