Cancer is the second biggest cause of death worldwide. Despite a number of studies being conducted, the effective mechanism for treating cancer has not yet been fully understood. The tumor-microenvironment such as hypoxia, low nutrients could disturb function of endoplasmic reticulum (ER) to maintain cellular homeostasis, ultimately leading to the accumulation of unfolded proteins in ER, so-called ER stress. The ER stress has a close relation with cancer. ER stress initiates unfolded protein response (UPR) to re-establish ER homeostasis as an adaptive pathway in cancer. However, persistent ER stress triggers the apoptotic pathway.
Therefore, blocking the adaptive pathway of ER stress or facilitating the apoptotic pathway could be an anti-cancer strategy. Recently, natural products and their derivatives have been reported to have anti-cancer effects via ER stress. Here, we address mechanisms of ER stress-mediated apoptosis and highlight strategies for cancer therapy by utilizing ER stress. Furthermore, we summarise anti-cancer activity of the natural products via ER stress in six major types of cancers globally (lung, breast, colorectal, gastric, prostate and liver cancer). This review deepens the understanding of ER stress mechanisms in major cancers as well as the suppressive impact of natural products against cancers via ER stress.
The mechanisms of cancer occurrence and progression are not fully understood yet. The proliferation of cancer originated from its ability to avoid programmed cell death, so-called apoptosis . That is why induction of apoptosis in cancer has been identified as a target for treatment of cancer [5,6]. Up to now, induction of apoptosis is conducted by two main apoptotic pathways: intrinsic and extrinsic pathway . Intrinsic pathway is mitochondria-mediated apoptosis which is mediated by cytochrome C release and activation of caspase-9, stimulating effector caspases, caspase-3. Extrinsic pathway is death receptor (DR)-mediated apoptosis DR5 which activates the FAS-associated death domain (FADD) and forms the death-inducing signaling complex (DISC), which processes downstream caspases including caspase-8,-7,-6, and -3 [8,9]. However, studies have identified that the accumulation of unfolded proteins in endoplasmic reticulum (ER) and its cellular stress response is involved in apoptosis, indicating influence of ER on cell fate as a third subcellular compartment .
Overview of ER Stress; A Double-Edged Sword-Cell Survival or Death?
ER is an organelle in the eukaryotic cell that is responsible for protein synthesis and calcium (Ca2+) signaling . It also provides a suitable environment for lipid, steroid, and cholesterol biosynthesis. Moreover, the main roles of ER include maintenance of homeostasis in intracellular Ca2+ storage and the folding of protein destined to be secreted on the plasma membrane . Proteins are translocated into ER lumen and undergo post translational modification for fidelity of synthesis, folding and correcting function. After passing ER, proteins are properly folded by a network of chaperones .
However, extra-cellular environmental challenges such as reactive oxygen species (ROS), hypoxia, and nutrients deprivation could induce disturbance in cellular redox regulation of ER, leading to an imbalance in homeostasis. Thus, the physiological function of ER and the ER protein-folding environment are impaired, ultimately resulting in the accumulation of unfolded protein in the lumen of the ER-namely, ER stress . Prior studies have demonstrated that both ER stress and the activation of unfolded protein response (UPR) are associated with pathologic processes, including neurodegenerative diseases, cardiovascular disease, and cancer .
Because of the rapid expansion of malignant neoplasm, cancer cells are exposed to low nutrients, poor vascularization, and hypoxia so that ER stress-related proteins including glucose-regulated protein 78 (GRP78)/binding protein (BiP), glucose-regulated protein 94 (GRP 94), ER associated degradation (ERAD), protein disulphide isomerase (PDI), activating transcription factor 6 (ATF6), inositol-requiring protein 1 (IRE1), α-x-box binding protein 1 (XBP1), protein kinase RNA-like ER kinase (PERK) and eukaryotic initiation factor 2 (eIf2α) are overexpressed in many types of cancer cells [15,16,17]. In response to ER stress on early phase, the cell initiates UPR to modulate proper protein folding and degradation of unfolded protein as an adaptive pathway for survival.
Under ER stress, GRP78/BiP, which originally binds to the luminal domain of three ER transducer sensors: IRE1, PERK, and ATF6, dissociates from these three ER transducer sensors. The three ER-localized transmembrane signal-transducers of UPR; ATF6, IRE1 and PERK detect accumulation of unfolded proteins and initiate to restore and maintain the ER homeostasis . Moreover, ERAD is increased to attenuate unfolded protein accumulation, enhancing protein folding capacity in ER and ER chaperones (GRP 94, GRP78/BiP, calnexin), which are elevated to stabilize protein folding. However, if ER stress is prolonged to the extent that UPR is unable to cope with unfolded proteins, UPR is promoted to be turned into apoptotic machineries by transducing apoptotic downstream pathways through ATF6, PERK, and IRE1 signaling pathways .
The standardized treatments of cancer consist of surgery, chemotherapy, radiation therapy and immunotherapy. These are utilized in accordance with the characters and stages of the cancers. Although the main purpose of anti-cancer treatments is to kill the cancer cells without damaging normal cells, cancer treatments possess limited efficacy and exert their actions on both malignant and normal cells, resulting in adverse effects on patients, including anemia, loss of appetite, delirium and peripheral neuropathy. Thus, the development of effective treatment which has anti-cancer activity with less adverse effects is still needed [94,95]. From the history of drug discovery, natural product-derived compounds could be a promising treatment due to their characteristic to induce apoptosis more commonly in cancers compared to normal cells [96,97].
In fact, several conventional chemotherapeutic agents including Taxol, epothilones, vinca alkaloids originate from the resource of natural products . Currently, as ER stress response is proven to have both an adaptive pathway and apoptotic pathway, modulation of ER stress could be an anti-cancer strategy. Therefore, researchers have focused on the interplay between natural products and anti-cancer effect via ER stress in malignant cells in vitro and in vivo [99,100,101]. Hence, in this review article, anti-cancerous mechanisms of natural products on the most common cancer types via modulation of ER-stress are discussed; lung, breast, colorectal, gastric, prostate, liver cancer, which represent 55% of the global incidence burden in 2012 [2,3].
As a way of cancer treatment, natural product-derived compounds are being introduced to the medical research and conducted to test the efficacy against cancers [168,169]. Especially, researches focusing on the cross link between the natural product or its derived compound and apoptosis in cancer via ER stress, are gaining interest [170,171].
Natural products or their bioactive compounds not only trigger apoptosis but also lower the resistance to chemotherapies via modulating ER stress. For example, brefeldin A derived from Eupenicillium brefeldianum was proven as an ER stress-inducing agent to overcome one of the standard drugs for leukemia fludarabine . Also, Pae, which is derived from Pycnostelma paniculatum K. Schum, lowers the resistance of doxorubicin . Furthermore, natural compounds were demonstrated to induce a synergistic effect with current standard therapies through ER stress regulation. For instance, Epigallocatechin 3-gallate, a polyphenolic green tea component, increased the apoptotic activity of temozolomide in glioblastoma cell death through inhibition of GPR78/BiP . And falcarindiol, a natural polyyne in dietary plants, was identified to induce a synergistic effect with 5-Fluorouracil and bortezomib on suppressing breast cancer via upregulation of CHOP .
Extracts taken from the review paper:
Anti-Cancer Natural Products and Their Bioactive Compounds Inducing ER Stress-Mediated Apoptosis: A Review
Citrate Suppresses Tumor Growth in Multiple Models through Inhibition of Glycolysis, the Tricarboxylic Acid Cycle and the IGF-1R Pathway
Citrate exhibits negative feedback on glycolysis2 and on the enzyme pyruvate dehydrogenase3,4 Conversely, inhibition of glycolysis suppresses tumor growth and can contribute to CD8+ T cell maturation28. Therefore, we hypothesized that citrate-mediated AKT inhibition might down regulate glycolysis.