The activated hepatic stellate cells (HSCs) are the major cells that secrete the ECM proteins and drive the pathogenesis of fibrosis in chronic liver disease. Targeting of HSCs by modulating their activation and proliferation has emerged as a promising approach in the development of anti-fibrotic therapy. Sorafenib, a multi-kinase inhibitor has shown anti-fibrotic properties by inhibiting the survival and proliferation of HSCs. In present study we investigated sorafenib induced cytoplasmic vacuolation mediated decreased cell viability of HSCs in dose and time dependent manner. In this circumstance, sorafenib induces ROS and ER stress in HSCs without involvement of autophagic signals. The protein synthesis inhibitor cycloheximide treatment significantly decreased the sorafenib-induced cytoplasmic vacuolation with increasing cell viability. Antioxidant human serum albumin influences the viability of HSCs by reducing sorafenib induced vacuolation and cell death. However, neither caspase inhibitor Z-VAD-FMK nor autophagy inhibitor chloroquine could rescue the HSCs from sorafenib-induced cytoplasmic vacuolation and cell death. Using TEM and ER organelle tracker, we conclude that the cytoplasmic vacuoles are due to ER dilation. Sorafenib treatment induces calreticulin and GPR78, and activates IRE1α-XBP1s axis of UPR pathway, which eventually trigger the non-apoptotic cell death in HSCs. This study provides a notable mechanistic insight into the ER stress directed non-apoptotic cell death with future directions for the development of efficient anti-fibrotic therapeutic strategies.

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The tumor suppressor p53 when undergoes amyloid formation confers several gain-of-function (GOF) activities that affect molecular pathways crucial for tumorigenesis and progression like some of the p53 mutants. Even after successful cancer treatment, metastasis and recurrence can result in poor survival rates. The major cause of recurrence is mainly the remnant cancer cells with stem cell-like properties, which are resistant to any chemotherapy treatment. Several studies have demonstrated the role of p53 mutants in exacerbating cancer stemness properties and epithelial-mesenchymal transition in these remnant cancer cells. Analyzing the amyloid/mutant p53-mediated signaling pathways that trigger metastasis, relapse or chemoresistance may be helpful for the development of novel or improved individualized treatment plans. In this review, we discuss the changes in the metabolic pathways such as mevalonate pathway and different signaling pathways such as TGF-β, PI3K/AKT/mTOR, NF-κB and Wnt due to p53 amyloid formation, or mutation. In addition to this, we have discussed the role of the regulatory microRNAs and lncRNAs linked with the mutant or amyloid p53 in human malignancies. Such changes promote tumor spread, potential recurrence, and stemness. Importantly, this review discusses the cancer therapies that target either mutant or amyloid p53, restore wild-type functions, and exploit the synthetic lethal interactions with mutant p53.