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  • tranylcypromine NOXA a BH only protein is best known

    2023-05-17

    NOXA, a BH3-only protein, is best known as a selective inhibitor of MCL-1, which is a highly expressed pro-survival protein in many human malignancies [30]. In addition, NOXA was recently proven to act as a direct activator via directly binding to BAX to induce apoptosis [31]. Given that its levels are regulated at both the transcriptional and post-translational levels, the drug discovery process for NOXA inducers could include developing transcriptional activators, such as an inducer of p53, or by targeting NOXA degradation. Previous studies have shown that NOXA is degraded by the 26S proteasome via K11-linked poly-ubiquitination by the CRL5 E3 ligase [13,14]. Indeed, both a proteasome inhibitor, bortezomib [32], and a CRL inhibitor, MLN4924 [[33], [34], [35], [36], [37], [38]], can stabilize the protein levels of NOXA to induce cancer cell apoptosis, which partially explains the anticancer activities of these drugs. The upregulation of NOXA induced by bortezomib indicates that increased NOXA in tranylcypromine is subjected to proteasome-dependent degradation prior to autophagy activation, suggesting that induction of NOXA as therapeutic strategy by inhibition of autophagy might combine proteasome inhibitor to achieve better efficacy. In addition, the induced NOXA sequentially acts as both apoptosis and autophagy inducer. In our study, we found that autophagy can also degrade NOXA, which may abrogate the anticancer effect of bortezomib and lead to drug resistance. Given that autophagy generally serves as a pro-survival pathway, autophagy inhibition or targeting NOXA autophagic degradation could be a novel strategy for inducing NOXA. The combination anticancer drugs, such as bortezomib and MLN4924, with autophagy inhibitors, such as chloroquine, may boost NOXA induction and be more effective at killing cancer cells via enhancing NOXA-mediated apoptosis. In summary, our study supports the following model. Autophagy selectively degrades NOXA via its adaptor protein p62 by binding to ubiquitinated NOXA at K35/K41/K48 to suppress NOXA-induced apoptosis. Inhibiting autophagy by molecule inhibitors or knocking down genes required for autophagy induces NOXA-dependent apoptotic cell death. p53 further amplifies autophagy inhibition-induced apoptosis through transactivating NOXA (Fig. 6). Our study demonstrates that autophagy inhibition enhances apoptosis by inducing the accumulation of NOXA, suggesting that autophagy inhibitors could be an effective therapy that induces NOXA-mediated apoptosis in cancer, especially wild-type p53-containing cancer.
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    Introduction Autophagy is defined as a catabolic process that is conserved among all eukaryotic organisms. The study of autophagy has gained immense importance in the past decade by defining the basic functioning of cellular and organismal metabolism. From regulating the fundamental metabolic functions inside the cells to varied diseases, namely, aging, cancer, neurodegenerative disorders, and lysosomal disorders, autophagy has become the central regulating point in controlling the homeostasis of the human body. As an evolutionarily conserved process, autophagy, through the breakdown of proteins and peptides, has assisted the cells to adapt to myriad stress conditions by providing a pool of amino acids. Hence, autophagy maintains the cellular homeostasis, thereby enabling the cells to stride past the crisis situations. Autophagy, at the basal level, regulates the intracellular conditions through cytoplasmic turnover of proteins and organelles. In some cases, accumulation of ubiquitinated proteins has been reported inside the cells upon deletion of certain autophagic proteins, such as Atg5 and Atg7, suggesting the indispensable role that autophagy plays in regulating the protein turnover of the cells [1]. Nonetheless, autophagy is important in maintaining cell growth and development. For instance, some mutant yeasts defective in autophagy displayed impaired spore formation [2]. Moreover, recent investigations have articulated the concept of selective autophagy. Autophagy has also been revealed to recognize specific substrates, mitochondria, lipid droplets, and peroxisomes resulting in their overall turnover. Despite its role in controlling the protein turnover of the cell, autophagy has also been investigated to play a crucial role in innate immunity. Autophagy facilitates the binding of endogenous antigens with major histocompatability complex-II (MHC-II) molecules that are recognized by CD4 + T cells. For example, in an experiment where influenza antigen was fused to LC3, it was efficiently incorporated into the autophagolysosomes and presented along with MHC-II class [3].