{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPAWR – also known as Prostate Apoptosis Response‐4 (Par-4) – functions as a central proapoptotic tumor suppressor that is widely expressed in both neural and epithelial tissues. In neurons and astrocytes, as well as in many cancer cells, PAWR is induced following a variety of stresses – including amyloid peptide exposure, trophic factor withdrawal, and chemotherapeutic insults – and its activation triggers caspase‐dependent apoptosis. In several studies, increased PAWR/Par-4 expression was found to be closely associated with mitochondrial dysfunction and apoptotic signaling, while blockade or down‐regulation of PAWR prevented apoptosis in models of Alzheimer’s disease and prostate cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, PAWR operates through both intracellular and extracellular mechanisms. Intracellularly, a distinct domain (the SAC domain) and critical nuclear localization signals enable PAWR to inhibit NF-κB activity and modulate apoptosis via the Fas death pathway. Its apoptotic function is further fine-tuned by post-translational modifications – for example, phosphorylation at a key residue (T155) by protein kinase A, which amplifies its cancer-selective apoptotic activity – and by interactions with other proteins. Notably, PAWR is subject to regulation by specific protein complexes, such as those involving THAP1 or RASSF2, and is targeted for ubiquitin-mediated degradation via its association with the E3 ligase Fbxo45. In addition, extracellular PAWR secreted from cells has been shown to bind to the cell-surface receptor GRP78 to induce apoptosis in a paracrine fashion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "11"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPAWR expression and function are frequently impaired in human cancers through a variety of oncogenic and epigenetic mechanisms. Oncogenic Ras, for instance, has been shown to downregulate PAWR expression via promoter methylation, contributing to cellular transformation in pancreatic and other epithelial tumors. In endometrial and breast cancers, epigenetic silencing – sometimes regulated by the EMT transcription factor Twist – results in reduced nuclear PAWR levels, which in turn facilitates tumor recurrence by allowing cancer cells to evade PAWR-dependent apoptosis. These observations highlight how loss or inactivation of PAWR is a common event that cooperates with other tumorigenic alterations, such as PTEN loss, to drive malignant progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "17"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in cell death, PAWR modulates several other signaling pathways that are critical for cancer cell survival and therapeutic sensitivity. For example, as an androgen receptor coactivator, PAWR enhances receptor-DNA interactions to regulate targets such as c-FLIP in prostate cells. It also acts as a negative regulator of Akt signaling in lung carcinomas and directly binds topoisomerase I to limit DNA relaxation and gene transcription, thereby suppressing transformation. In addition, PAWR has been implicated in sensitizing tumor cells to chemotherapy – its expression is modulated by factors such as microRNAs (e.g. miR-107 in colorectal cancer) and even by agents like arsenic trioxide – and nutritional components like vitamin E analogues have been shown to upregulate PAWR, thereby attenuating inflammatory chemokine production."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "25"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn summary, PAWR/Par-4 is a multifaceted apoptosis inducer whose proper localization, post-translational modification, and interaction with key signaling partners are essential for its tumor suppressor functions. Its selective activation in cancer cells – whether via intracellular signaling cascades or through its extracellular engagement with receptors such as GRP78 – underpins its emerging potential as a therapeutic target. Recent reviews underscore the promise of harnessing PAWR’s SAC domain for cancer-selective therapy, as well as the need to overcome oncogenic mechanisms that impair its expression in diverse tumor types."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": ""}]}]}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Q Guo, W Fu, J Xie, et al. 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