Crosstalk between autophagy and proteasome protein degradation systems: possible implications for cancer therapy

Abstract

Abstract:The Ubiquitin-Proteasomes System (UPS) and autophagy, two main intracellular protein degradation pathways within the eukaryotic cells which were originally regarded as rather independent, seem to be very closely related. Proteasome inhibitors, including the multipathway inhibitor bortezomib, are drawing increased attention for their therapeutic potential in the treatment of chronic inflammation and cancer, especially tumours with a high degree of malignancy. The over-activation of autophagy induces cell death and may act as a powerful tumour-suppressing mechanism. However, autophagy, serving as an important mechanism to generate nutrients in time of cellular stresses, may directly contribute to the survival of cells treated with proteasome inhibitors, and in consequence, may decrease the effectiveness of therapy. Results of studies performed on several cancer cell lines demonstrated synergy between proteasome inhibitors and autophagy inhibitors. Those results became the base for ongoing clinical trials investigating autophagy inhibition in combination with anti-cancer therapies, including bortezomib. This review provides summary of the latest data on the functioning of the UPS and the mechanisms of autophagy. The new insights describing the main pathways of autophagy activation in response to UPS inhibition related to: (i) Unfolded Protein Response, (ii) PI3K/Akt/mTOR pathway, and (iii) formation of aggresomes, are discussed. It is concluded that concomitant inhibition of the two main cellular protein degradation systems may provide new therapeutic modalities for cancer treatment.

Inhibition of autophagy promotes cell apoptosis induced by the proteasome inhibitor MG-132 in human esophageal squamous cell carcinoma EC9706 cells

“…The proteasome system and autophagy machinery are regarded as the two major cellular protein degradation systems (3). It has been identified that proteasome inhibitor-induced autophagy is able to control endoplasmic reticulum stress and reduce cell death in cancer cells by activating the downstream inositol-requiring enzyme-1/c-Jun NH2-terminal kinase pathway (18).…”

“…UPS-mediated proteolysis affects several different proteins through proteasome-mediated degradation, which is involved in the regulation of the cell cycle, apoptosis and cellular differentiation (2). Therefore, targeting this pathway using proteasome inhibitors may represent a novel approach for the treatment of cancer (3). A number of previous studies have demonstrated that proteasome inhibitors can induce tumor cell death via inhibiting proteasome activity (4,5).…”

Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6

“…Contrastingly, autophagy serves as an important mechanism to generate nutrients under cellular stress and may directly contribute to the cell survival following treatment with anticancer drugs. Autophagy may ultimately decrease the effect of anticancer therapies [13]. Therefore, autophagy appears to have a dual role in cancer therapy.…”

“…There are 2 intracellular protein degradation pathways in eukaryotic cells: UPS and autophagy [13]. Inhibition of proteasomal activity or treatment with IR induces autophagy but not apoptosis in cancer cells [14][15][16].…”

Reduced level of synapsin I protein in the rat striatum after intraventricular administration of proteasome inhibitors: preliminary studies

“…It has been also proposed that, the synapsins may play a role in the formation and maintenance of synapses (synapsin I and II), synaptic vesicle fusion (synapsin I, II, and III) and its protein stabilisation (synapsin I and II), neurite elongation (synapsin I, II, and III) and neurogenesis (synapsin III) [24]. Lately, it has been postulated that synapsin cellular turnover is regulated by the ubiquitin-proteasome system (UPS) [6,14], the main system responsible for protein degradation in eukaryotic cells, which has currently become attractive research topic due to its involvement in neurodegenerative pathogenesis during aging, the inflammatory response, and the dynamics of tumour development [22,26].…”