The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies

Abstract

Cancer progression is characterized by rapidly proliferating cancer cells that are in need of increased protein synthesis. Therefore, enhanced endoplasmic reticulum (ER) activity is required to facilitate the folding, assembly and transportation of membrane and secretory proteins. These functions are carried out by ER chaperones. It is now becoming clear that the ER chaperones have critical functions outside of simply facilitating protein folding. For example, cancer progression requires GRP78 for cancer cell survival and proliferation, as well as angiogenesis in the microenvironment. GRP78 can translocate to the cell surface acting as a receptor regulating oncogenic signaling and cell viability. Calreticulin, another ER chaperone, can translocate to the cell surface of apoptotic cancer cells and induce immunogenic cancer cell death and antitumor responses in vivo. Tumor-secreted GRP94 has been shown to elicit antitumor immune responses when used as antitumor vaccines. Protein disulfide isomerase is another ER chaperone that demonstrates pro-oncogenic and pro-survival functions. Due to intrinsic alterations of cellular metabolism and extrinsic factors in the tumor microenvironment, cancer cells are under ER stress, and they respond to this stress by activating the unfolded protein response (UPR). Depending on the severity and duration of ER stress, the signaling branches of the UPR can activate adaptive and pro-survival signals, or induce apoptotic cell death. The PERK signaling branch of the UPR has a dual role in cancer proliferation and survival, and is also required for ER stress-induced autophagy. The activation of the IRE1α branch promotes tumorigenesis, cancer cell survival, and regulates tumor invasion. In summary, perturbance of ER homeostasis plays critical roles in tumorigenesis, and therapeutic modulation of ER chaperones and/or UPR components presents potential antitumor treatments.

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

“…Pieces were placed in 30 mM EDTA/PBS for 30 min, passed through a 100-µm cell strainer, and centrifuged, RNA was isolated from crypts, and RT-qPCR was performed as described below. (Luo and Lee, 2013); Xbp1-deficient tumor cells exhibit impaired growth when xenografted into Scid mice (RomeroRamirez et al, 2004(RomeroRamirez et al, , 2009, and disruption of Ire1/Xbp1 signaling may be exploited pharmacologically for the treatment of multiple myeloma (Lee et al, 2003;Mimura et al, 2012). Our data imply an unexpected tumor-preventive role of Xbp1 in the intestinal epithelium.…”

“…Human tumor cells indeed exhibit evidence of ER stress, and reduced capacity to elicit an UPR within malignant cells results in decreased tumorigenesis in model systems (Ma and Hendershot, 2004;Bi et al, 2005;Fu et al, 2008;Luo and Lee, 2013). Xbp1 has been considered protumorigenic sustained, augments tumor formation in both an inflammatory (i.e., CAC after DSS/AOM) and noninflammatory (i.e., CRC in Apc min mice) context.…”

“…Malignant cells are commonly exposed to hypoxia, nutrient deprivation, and pH changes that impact protein folding (Ma and Hendershot, 2004;Hetz et al, 2011;Luo and Lee, 2013). Human tumor cells indeed exhibit evidence of ER stress, and reduced capacity to elicit an UPR within malignant cells results in decreased tumorigenesis in model systems (Ma and Hendershot, 2004;Bi et al, 2005;Fu et al, 2008;Luo and Lee, 2013).…”

Insulin-like growth factor binding protein-3 (IGFBP-3): Novel ligands mediate unexpected functions

“…This interaction has also been detected in a yeast 2-hybrid screen (Li, et al 2012). Because an important function of GRP78 is as an endoplasmic reticulum chaperone, coordinating the cellular response to protein misfolding (Luo and Lee 2013), the involvement of IGFBP-3 in this process was sought, but IGFBP-3 was not implicated in any pathway of unfolded protein response signaling (Grkovic et al 2013). GRP78 has also been shown to be required for stress-induced autophagy , and an investigation of the possible role for the IGFBP-3-GRP78 interaction in this process in breast cancer cells revealed that IGFBP-3 could enhance the survival of cells subjected to glucose starvation and hypoxia in a GRP78-dependent manner (Grkovic et al 2013).…”

Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression

“…The UPR plays important roles in tumorigenesis, therapy resistance, and cancer progression (14,32). Moderate and transient UPR activation by E 2 and other activators promotes an adaptive stress response, which increases UPR expression and confers protection from subsequent exposure to higher levels of cell stress (14,33).…”