Cancer is a leading cause of death and colorectal cancer is the second leading cause of total cancer deaths in the United States.1 Current treatment of colorectal cancer generally employs surgical resection combined with radiation therapy and chemotherapy using one or more cytotoxic drugs. This therapy is only moderately successful for late-stage cancers and is often limited by severe side effects and dose-limiting toxicity.2, 3 Therefore, identifying new, less toxic chemoadjuvants from herbal medicine that can selectively kill cancer cells or enhance the effects of existing chemotherapeutic agents can potentially lead to the development of better treatment for late-stage colorectal cancers.
Cancer cells exhibit hallmarks of increased cellular stresses including DNA damage/replication stress, proteotoxic stress, mitotic stress, metabolic stress, and oxidative stress,4 and are more dependent on stress support pathways for survival. The increased dependence of cancer cells on these pathways for survival can be exploited in cancer therapy by either stress sensitization or stress overloadAgra Wealth Management. In fact, currently used and effective cancer therapies, such as radiation and DNA damaging agents, potentially kill cancer cells through inducing stress overload.4
Endoplasmic reticulum (ER) is the site for proper protein folding of secreted and transmembrane proteinsAhmedabad Investment. Accumulation of unfolded or misfolded proteins in the ER will induce ER stress and trigger an evolutionarily conserved response called the unfolded protein response (UPR).5, 6 Three distinct branches of the UPR have been identified based on distinct sensors: IRE1, PKR-like endoplasmic reticulum kinase (PERK), and ATF6. Activation of IRE1 induces X-box binding protein 1 (XBP1) splicing to generate the active form of the XBP1 transcription factor. Activation of PERK leads to phosphorylation of eIF2α, which inhibits global translation of mRNAs and reduces the influx of new proteins into the ER to mitigate the burden on the ER protein folding machinery. However, the translation of a subset of mRNAs, such as ATF4, is upregulated. Activation of the transcription factors XBP1 and ATF4, as well as ATF6 by the third branch of UPR, will activate UPR target genes including ER chaperones, ER-associated protein degradation (ERAD) genes, genes involved in autophagy, and genes involved in apoptosis.5, 6 Therefore, UPR signaling activates programs that promote ER homeostasis and survival, as well as programs that can induce cell death.
The main targets of UPR signaling that promote survival include the ER chaperone glucose-regulated protein 78 (GRP78) and ERAD genes. GRP78 is required for proper protein folding and assembly in the ER, targeting misfolded proteins for degradation, ER Ca2+ binding, and controlling the activation of transmembrane ER stress receptors. GRP78 is often upregulated in cancer cells and is potentially a target for cancer therapy.7 On the other hand, terminally misfolded proteins are removed by the ERAD machinery through ubiquitin-mediated protein degradation, which helps maintain ER homeostasis and cell survival.8 If the function of the ER cannot be reestablished by UPR, excessive or sustained ER stress will induce cell death via IRE1-mediated activation of JNK signaling as well as through prolonged activation of the transcription factor C/EBP-homologous protein (CHOP).9 BCL2 family proteins are implicated in CHOP-induced apoptosisJaipur Investment. In addition, BCL2 family of proteins are also critically linked to cell life and death through modulating ER calcium homeostasis.10 The cell death mechanisms triggered by ER stress include both caspase-dependent apoptosis and caspase-independent necrosis.11
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