Endoplasmic Reticulum Stress and Unfolded Protein Response in Breast Cancer: The Balance between Apoptosis and Autophagy and Its Role in Drug Resistance

Abstract

The unfolded protein response (UPR) is a stress response activated by the accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER) and its uncontrolled activation is mechanistically responsible for several human pathologies, including metabolic, neurodegenerative, and inflammatory diseases, and cancer. Indeed, ER stress and the downstream UPR activation lead to changes in the levels and activities of key regulators of cell survival and autophagy and this is physiologically finalized to restore metabolic homeostasis with the integration of pro-death or/and pro-survival signals. By contrast, the chronic activation of UPR in cancer cells is widely considered a mechanism of tumor progression. In this review, we focus on the relationship between ER stress, apoptosis, and autophagy in human breast cancer and the interplay between the activation of UPR and resistance to anticancer therapies with the aim to disclose novel therapeutic scenarios. The hypothesis that autophagy and UPR may provide novel molecular targets in human malignancies is discussed.

Dexmedetomidine Alleviated Endoplasmic Reticulum Stress via Inducing ER-phagy in the Spinal Cord of Neuropathic Pain Model

“…Moreover, a disturbance in UPR pathway might render neurons vulnerable to neuropathic pain stimuli (Huang et al, 2015;Zhou et al, 2017;Kang et al, 2018). The link between autophagy and ER stress via UPR has been investigated substantially (Deegan et al, 2013;Huang et al, 2013;Lupachyk et al, 2013;Sisinni et al, 2019;Yang et al, 2019). PERK pathway is essential for autophagy induction following ER stress (Lee et al, 2019).…”

“…Cellular stress, free radical exposure, calcium depletion, and unfolded or misfolded protein accumulation in endoplasmic reticulum (ER) lumen lead to ER stress (Sisinni et al, 2019). Recent studies demonstrated that ER stress might be involved in the induction and maintenance of neuropathic pain (Ge et al, 2018).…”

“…ER stress leads to recruit glucose-regulated protein 78 (Grp78, a chaperone that is induced by the UPR and is also recognized as a regulator of UPR activation) and release UPR sensors: protein kinase RNAlike ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and ATF6. In this study, we examined PERK/activating transcription factor (ATF) 4, IRE-1/c-Jun N-terminal kinase (JNK), and ATF6 pathways to reveal the possible mechanism underlying UPR and autophagy (Sisinni et al, 2019).…”

Identification and Validation of an Individualized Autophagy-Clinical Prognostic Index in Gastric Cancer Patients

“…Autophagy can prevent apoptosis induced by antitumor drugs and promote tumor drug resistance. However, autophagy cell death may be a death mode of apoptosis tolerant tumor cells, Autophagy has double effects on drug resistance of tumor cells [30].…”

Network modeling of patients' biomolecular profiles for clinical phenotype/outcome prediction

“…the accumulation of unfolded/misfolded proteins in the reticulum, may arise due to glucose deficiency, hypoxia, calcium imbalance and oxidative stress. ERS is associated with tumor development and metastasis in breast cancer since the high cell proliferation rate in tumors causes hypoxia, www.nature.com/scientificreports www.nature.com/scientificreports/ nutrients starvation and higher ROS production 52,53 . In particular, increased ROS production in cancer cells arises from oxidative phosphorylation, oxygen metabolism and NADPH oxidase functions leading to oxidative stress, described also in breast cancer 54 .…”