Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells

Abstract

In contrast to normal tissue, cancer cells display profound alterations in protein synthesis and degradation. Therefore, proteins that regulate endoplasmic reticulum (ER) homeostasis are being increasingly recognized as potential therapeutic targets. The ubiquitin-proteasome system and autophagy are crucially important for proteostasis in cells. However, interactions between autophagy, the proteasome, and ER stress pathways in cancer remain largely undefined. This study demonstrated that withaferin-A (WA), the biologically active withanolide extracted from Withania somnifera, significantly increased autophagosomes, but blocked the degradation of autophagic cargo by inhibiting SNARE-mediated fusion of autophagosomes and lysosomes in human pancreatic cancer (PC) cells. WA specifically induced proteasome inhibition and promoted the accumulation of ubiquitinated proteins, which resulted in ER stress-mediated apoptosis. Meanwhile, the impaired autophagy at early stage induced by WA was likely activated in response to ER stress. Importantly, combining WA with a series of ER stress aggravators enhanced apoptosis synergistically. WA was well tolerated in mice, and displayed synergism with ER stress aggravators to inhibit tumor growth in PC xenografts. Taken together, these findings indicate that simultaneous suppression of 2 key intracellular protein degradation systems rendered PC cells vulnerable to ER stress, which may represent an avenue for new therapeutic combinations for this disease.

Hepatotoxicity Induced by Isoniazid-Lipopolysaccharide through Endoplasmic Reticulum Stress, Autophagy, and Apoptosis Pathways in Zebrafish

“…An appropriate ERS-induced unfolded protein response (UPR) can upregulate the protein folding mechanism to attenuate stress and protect cells (16). However, strong or long-duration stress reactions will result in functional and metabolic disorders and cell and tissue injury (17). Many studies have indicated that ERS development is closely associated with liver diseases, such as nonalcoholic fatty liver disease, viral hepatitis, liver cancer, and drug-induced liver injury.…”

Penfluridol induces endoplasmic reticulum stress leading to autophagy in pancreatic cancer

“…8 It has been demonstrated that Withaferin A, a biologically active withanolide extracted from Withania somnifera induces apoptosis in pancreatic cancer through ER stress-mediated autophagy. 9 In another study, penfluridol was shown to inhibit pancreatic cancer by activation of protein phosphatase 2A. 10 Recently, we have demonstrated that penfluridol, an antipsychotic drug, suppresses pancreatic tumor growth by autophagy-mediated apoptosis.…”

Endoplasmic reticulum stress and the protein degradation system in ophthalmic diseases

“…Both the UPS and autophagy play important roles in maintaining the balance of cellular proteins, and each has its own advantages. The UPS is responsible for the degradation of both short-lived proteins and misfolded proteins, while autophagy can degrade misfolded proteins and damaged organelles (Li et al, 2016). It was found that there is a certain relationship between the UPS and autophagy.…”