Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers

Abstract

The unfolded protein response (UPR) is an adaptive cellular program used by eukaryotic cells to cope with protein misfolding stress. During tumor development, cancer cells are facing intrinsic (oncogene activation) and extrinsic (limiting nutrient or oxygen supply) challenges, with which they must cope to survive. Moreover, chemotherapy represents an additional extrinsic challenge that cancer cells are facing and to which they adapt in the case of resistance. As of today, resistance to chemotherapy and targeted therapies is one of the important issues that oncologists have to deal with for treating cancer patients. In this review, we first describe the key molecular mechanisms controlling the UPR and their implication in solid cancers. Then, we review the literature that connects cancer chemotherapy resistance mechanisms and activation of the UPR. Finally, we discuss the possible applications of targeting the UPR to bypass drug resistance.

GRP78‐mediated antioxidant response and ABC transporter activity confers chemoresistance to pancreatic cancer cells

“…As the cancer cells undergo rapid proliferation, the need for increased protein and other bimolecular synthesis contributes to an increased ER stress response in cancer cells (Avril et al ., 2017; Lee, 2007). The ER is the main site for the translation of excess nutrition into metabolic and inflammatory responses.…”

“…The unfolded protein response (UPR) contributes to chemoresistance, a homeostatic mechanism, which ameliorates stressful conditions to ensure cell survival. To survive the pressure created by the tumor microenvironment, including hypoxia and nutrient deprivation, tumor cells utilize the UPR pathways (Avril et al ., 2017; Chevet et al ., 2015; Lee, 2007; Ma and Hendershot, 2004). Multiple components of the UPR have been linked to advanced tumor stage and chemoresistance in cancer (Lee, 2014; Roller and Maddalo, 2013; Shen et al ., 2017; Wang and Kaufman, 2014).…”

“…XBP1s also correlates with higher tumor grade, chemoresistance, and shorter survival in lymphoma (Wang and Kaufman, 2014). GRP78, the regulator of the UPR, has previously been correlated with poor patient prognosis in multiple cancers, including pancreatic cancer (Avril et al ., 2017; Gifford et al ., 2016; Ma and Hendershot, 2004; Niu et al ., 2015; Wang and Kaufman, 2014). Based on correlation studies and direct overexpression leading to chemoresistance, numerous proteins in the UPR pathway have been targeted with small molecules in hopes to attenuate chemoresistance (Chevet et al ., 2015; Gifford et al ., 2016; Lee, 2014; Roller and Maddalo, 2013).…”

“…NRF2 normally acts like a tumor suppressor, but overactivation of its antioxidant response elements (ARE) activity leads to cell survival of normal and malignant cells (Chartoumpekis et al ., 2015; DeNicola et al ., 2011; Menegon et al ., 2016). It has previously been reported that gemcitabine upregulates the NRF2 pathway, helping to mediate resistance (Avril et al ., 2017; Palam et al ., 2015). …”

Squamous Cell Carcinoma Antigen-encoding Genes SERPINB3/B4 as Potentially Useful Markers for the Stratification of HNSCC Tumours

“…In epithelial cells from various types of adenocarcinomas, the introduction of an activated RAS oncogene was found to induce SERPINB3/SERPINB4 expression, leading to endoplasmic reticulum stress and a cellular homeostatic response known as the unfolded protein response (UPR) (17,18). Through its ability to neutralize intracellular proteases and to induce the UPR, SERPINB3 may contribute to the installation of a pro-inflammatory phenotype characterized by high expression of the cytokine interleukin-6 (IL6) in colorectal and pancreatic adenocarcinomas (15).…”