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 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.

Figure 1

Unfolded protein response and its regulation on cell activities. Left panel: Under non-stress condition, ER lumenal GRP78, in addition to folding proteins, binds to IRE1α, ATF6, PERK and caspase-12 and -7, quenching their activation. Right panel: When cells are under ER stress, GRP78 is titrated away through binding to the malfolded proteins, resulting in activation of the IRE1α, ATF6 and PERK signaling pathway. IRE1α activates its RNase activity to cleave the mRNA of XBP1, resulting in a spliced form of XBP1 (XBP1-s). ATF6 translocates from the ER to the Golgi apparatus, where it is cleaved into the active nuclear form ATF6(N). PERK dimerizes and autophosphorylates, and thereby phosphorylates its two major substrates eukaryotic translation initiation factor 2α (eIF2α) and nuclear factor-like 2 (Nrf2). eIF2α phosphorylation attenuates global protein synthesis, and inhibits cyclin D1 translation through which contributes to cell cycle arrest. The phosphorylation of eIF2α also activates the transcription of ATF4. XBP1(s), ATF6(N) and ATF4 act in concert to induce transcription of target genes mediating protein folding and degradation. Autophagy is also triggered. Another function of phosphorylated eIF2α is to activate CHOP which promotes apoptosis. The phosphorylation of Nrf2 activates the expression of enzymes required for ROS quenching, and thereby inhibits ROS accumulation. Procaspase-12 and -7, upon released from GRP78, are cleaved into their activated forms triggering apoptosis.

Figure 2

The vicious circle of ER stress and unfolded protein response in promoting tumor progression. Cancer cells are under ER stress due to the growth signaling and factors from the microenvironments. Adaptive UPR is activated to support tumor cell survival and growth. Cancer cells under ER stress secrete proangiogenic factors to stimulate the proliferation of endothelial cells, which in return promotes cancer cell survival and tumor growth. Cancer cells under ER stress also secrete proinflammatory signals to the stromal cells in the vicinity, mostly tumor-associated macrophages, which in turn are activated and secrete inflammatory cytokines that promote tumor growth, angiogenesis, invasion and metastasis.

Figure 3

The different localizations and functions of major ER chaperones. The circle in the center indicates ER, where the majority of ER chaperones are located. The squares outside of ER indicate non-traditional localization of these chaperones and their functions.