GRP78/BiP alleviates oxLDL-induced hepatotoxicity in familial hypercholesterolemia caused by missense variants of LDLR in a HepG2 cellular model.

Background And Aims: The accumulation of misfolded proteins, encoded by genetic variants of functional genes leads to Endoplasmic Reticulum (ER) stress, which is a critical consequence in human disorders such as familial hypercholesterolemia, cardiovascular and hepatic diseases. In addition to the identification of ER stress as a contributing factor to pathogenicity, extensive studies on the role of oxidized Low-Density Lipoprotein (oxLDL) and its ill effects in expediting cardiovascular diseases and other metabolic comorbidities are well documented. However, the current understanding of its role in hepatic insults needs to be revised.

Proteostasis Regulation in the Endoplasmic Reticulum: An Emerging Theme in the Molecular Pathology and Therapeutic Management of Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal genetic disease characterized by high serum low-density lipoprotein (LDL) content leading to premature coronary artery disease. The main genetic and molecular causes of FH are mutations in low-density lipoprotein receptor gene () resulting in the non-clearance of LDL from the blood by hepatocytes and consequently the formation of plaques. LDLR is synthesized and glycosylated in the endoplasmic reticulum (ER) and then transported to the plasma membrane via Golgi.

Linking genotoxicity and cytotoxicity with membrane fluidity: A comparative study in ovarian cancer cell lines following exposure to auranofin.

Auranofin, an organogold compound classified as an anti-rheumatic agent is under phase 2 clinical trials for re-purposing to treat recurrent epithelial ovarian cancer. We have reported earlier that Breast cancer 1, early onset (BRCA1) mutant ovarian cancer cells exhibit increased sensitivity to auranofin. BRCA1 is a DNA repair protein whose functional status is critical in the prognosis of ovarian cancer.

BRCA1 deficiency increases the sensitivity of ovarian cancer cells to auranofin.

Auranofin, a thioredoxin reductase inhibitor and an anti-rheumatic drug is currently undergoing phase 2 clinical studies for repurposing to treat recurrent epithelial ovarian cancer. Previous studies have established that auranofin exerts its cytotoxic activity by increasing the production of reactive oxygen species (ROS). Breast cancer 1, early onset (BRCA1) is a DNA repair protein whose functional status is critical in the prognosis of ovarian cancer.

Down-regulation of PERK enhances resistance to ionizing radiation.

Although, ionizing radiation (IR) has been implicated to cause stress in endoplasmic reticulum (ER), how ER stress signaling and major ER stress sensors modulate cellular response to IR is unclear. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) is an ER transmembrane protein which initiates unfolded protein response (UPR) or ER stress signaling when ER homeostasis is disturbed. Here, we report that down-regulation of PERK resulted in increased clonogenic survival, enhanced DNA repair and reduced apoptosis in irradiated cancer cells.

Atypical heat shock response and acquisition of thermotolerance in P388D1 cells.

Reports of atypical heat shock response in some tumour cell lines emphasize the possibilities of alternate stress response mechanisms. We demonstrate here that P388D1, a mouse macrophage tumour cell line, failed to induce heat shock proteins (HSPs) in response to either heat stress (42 °C, 1h) or to heavy metal stress induced by arsenic trioxide (5-20 μM). Heat shock transcriptional factor 1 (HSF1) that mediates transcriptional up regulation of HSPs during stress was found to be deficient in transactivation despite its binding to the promoter region of HSP genes.

KNK437, abrogates hypoxia-induced radioresistance by dual targeting of the AKT and HIF-1α survival pathways.

KNK437 is a benzylidene lactam compound known to inhibit stress-induced synthesis of heat shock proteins (HSPs). HSPs promote radioresistance and play a major role in stabilizing hypoxia inducible factor-1α (HIF-1α). HIF-1α is widely responsible for tumor resistance to radiation under hypoxic conditions.