The Unfolded Protein Response, Degradation from Endoplasmic Reticulum and Cancer

Abstract

The endoplasmic reticulum (ER) is an essential organelle involved in many cellular functions including protein folding and secretion, lipid biosynthesis and calcium homeostasis. Proteins destined for the cell surface or for secretion are made in the ER, where they are folded and assembled into multi-subunit complexes. The ER plays a vital role in cellular protein quality control by extracting and degrading proteins that are not correctly folded or assembled into native complexes. This process, known as ER-associated degradation (ERAD), ensures that only properly folded and assembled proteins are transported to their final destinations. Besides its role in protein folding and transport in the secretory pathway, the ER regulates the biosynthesis of cholesterol and other membrane lipids. ERAD is an important means to ensure that levels of the responsible enzymes are appropriately maintained. The ER is also a major organelle for oxygen and nutrient sensing as cells adapt to their microenvironment. Stresses that disrupt ER function leads to accumulation of unfolded proteins in the ER, a condition known as ER stress. Cells adapt to ER stress by activating an integrated signal transduction pathway called the unfolded protein response (UPR) (1). The UPR represents a survival response by the cells to restore ER homeostasis. If ER stress persists, cells activate mechanisms that result in cell death. Chronic ER stress is increasingly being recognized as a factor in many human diseases such as diabetes, neurodegenerative disorders and cancer. In this review we discuss the roles of the UPR and ERAD in cancer and suggest directions for future research.

Figure 1.

The unfolded protein response in mammalian cells. ER stress activates the unfolded protein response (UPR). The UPR acts to relieve ER stress, but prolonged UPR can also lead to cell death. There are at least 3 ER stress sensors on the ER membrane: IRE1α, PERK, and ATF6. Activated IRE1α splices an intron from XBP1 mRNA, producing XBP1s. XBP1 is a transcription factor that up-regulates many ER chaperones and genes involved in ERAD as well as membrane biogenesis. IRE1α also binds TRAF2 and activates ASK1 and downstream kinases, leading to activation of JNK and p38MAPK. JNK activation promotes autophagy and apoptosis; p38 promotes cell survival in a quiescence-like state. Activated PERK phosporylates eIF2α, resulting in inhibition of protein translation. However, some specific mRNAs, including ATF4, are translated under these conditions. ATF4 induces expression of genes involved in redox response, autophagy, and apoptosis. When activated, ATF6 translocates to the Golgi apparatus, where it is processed by Golgi proteases (S1P, S2P) to release the active transcription factor. ATF6 induces genes involved in ER homeostasis and membrane biogenesis.

Figure 2.

A model for studying the roles of UPR and ERAD in metastasis. (Top left) Hypoxia and ischemia in rapidly growing tumors induce the UPR, which is critical for tumor cell survival under these harsh conditions. The UPR has been implicated in EMT, an important early event that generates motile cells during metastasis. Tumor cells leaving the primary tumor enter the circulation to reach distant organs. During these stages, the UPR can act to promote tumor cell survival. Cell death and senescence that occur when tumor cells first extravasate to the secondary organs limit successful tumor cell colonization of the secondary site (top right and bottom left). ER stress may play an important role in these early events at the secondary site. Metastasis suppressors such as KAI1 induce senescence and apoptosis of tumor cells by both oxidative and ER stress mechanisms. Efficient ERAD can promote tumor cell survival and proliferation at the secondary site. Tumor cells may also enter dormancy until conditions favor their growth. As the micrometastases grow, lack of glucose and oxygen induces the UPR, which acts with the hypoxia response to induce angiogenesis to support growth into full-blown metastases (bottom right).