Role of the unfolded protein response in determining the fate of tumor cells and the promise of multi-targeted therapies

Abstract

Although there have been advances in our understanding of carcinogenesis and development of new treatments, cancer remains a common cause of death. Many regulatory pathways are incompletely understood in cancer development and progression, with a prime example being those related to the endoplasmic reticulum (ER). The pathological sequelae that arise from disruption of ER homeostasis are not well defined. The ER is an organelle that is responsible for secretory protein biosynthesis and the quality control of protein folding. The ER triggers an unfolded protein response (UPR) when misfolded proteins accumulate, and while the UPR acts to restore protein folding and ER homeostasis, this response can work as a switch to determine the death or survival of cells. The treatment of cancer with agents that target the UPR has shown promising outcomes. The UPR has wide crosstalk with other signaling pathways. Multi-targeted cancer therapies which target the intersections within signaling networks have shown synergistic tumoricidal effects. In the present review, the basic cellular and signaling pathways of the ER and UPR are introduced; then the crosstalk between the ER and other signaling pathways is summarized; and ultimately, the evidence that the UPR is a potential target for cancer therapy is discussed. Regulation of the UPR downstream signaling is a common therapeutic target for different tumor types. Tumoricidal effects achieved from modulating the UPR downstream signaling could be enhanced by phosphodiesterase 5 (PDE5) inhibitors. Largely untapped by Western medicine for cancer therapies are Chinese herbal medicines. This review explores and discusses the value of some Chinese herbal extracts as PDE5 inhibitors.

Keywords: Cancer; Endoplasmic reticulum stress; Phosphodiesterase 5 inhibitors; Signaling pathways; Unfolded protein response.

Fig. 1

Crosstalk between ER stress and other signaling pathways. Under ER stress, IRE1α activated GSK-3β phosphorylates mTORC2 on Ser1235, thereby hindering the binding between mTORC2 and the Ser473 site on Akt. This decreases the total amount of activated Akt, thus impairing the activation of mTORC1. Consequently, the mTORC1-initiated downstream anabolic metabolism, including protein synthesis, cell growth, and proliferation, is inhibited. The ER stress sensor, IRE1α, can be activated by the pro-apoptotic proteins, Bak, Bim, and PUMA. Upon stimulation, IRE1α induces the TRAF2/ASK1/JNK cascade, which contributes to cell death. While playing a core role in the IRE1α-initiated apoptotic signaling, ASK1 is also a member of the Raf family, which activates MEK4/MEK7-JNK signaling. This suggests that ASK1 is a coordinator in the interplay between the IRE1α-mediated apoptotic signaling and Ras/Raf/MEK/ERK signaling. GSK-3β glycogen synthase kinase-3, mTORC mTOR complex, TRAF2 tumor necrosis factor receptor (TNFR)-associated factor 2, ASK1 apoptosis signal-regulating kinase 1, JNK c-Jun amino-terminal kinase

Fig. 2

Dual roles of UPR in cancer. Cancer cells often live under hypoxic conditions which activate the IRE1 and PERK branches of the UPR to support cancer growth. On the one hand, cancer cells exploit the prosurvival UPR signaling to conquer the lethal effect of treatments. On the other hand, upregulated XBP1 induces the accumulation of triglyceride (TG) in dendritic cells, which decreases the expression of the major histocompatibility complex-1 (MHC1), thereby hindering the activation of CD8⁺ T cells. The immune sabotage of XBP1 contributes to a blunted immune elimination of cancer cells. In contrast, the G1 phase arrest of cancer cells is also related to the activation of the PERK branch of the UPR, suggesting that UPR has dual roles in determining the fate of cancer cells. TG triglyceride, CTL cytotoxic T lymphocyte, MCH1 major histocompatibility complex1, CDK cyclin dependent kinase