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
glucose regulated
protein (GRP) 78 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. Because of 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
protein kinase RNA-like ER
kinase 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
inositol-requiring
kinase 1α branch promotes
tumorigenesis,
cancer cell survival and regulates
tumor invasion. In summary, perturbance of ER homeostasis has critical roles in
tumorigenesis, and therapeutic modulation of ER chaperones and/or UPR components presents potential antitumor treatments.