Programmed cell death (PCD) is a fundamental biological process for maintaining cellular equilibrium and regulating development, health, and disease across all living organisms. Among the various type Show more
Programmed cell death (PCD) is a fundamental biological process for maintaining cellular equilibrium and regulating development, health, and disease across all living organisms. Among the various types of PCD, apoptosis plays a pivotal role in numerous diseases, notably cancer. Cancer cells frequently develop mechanisms to evade apoptosis, increasing resistance to standard chemotherapy treatments. This resistance has prompted extensive research into alternative mechanisms of programmed cell death. One such pathway is oncosis, characterized by significant energy consumption, cell swelling, dilation of the endoplasmic reticulum, mitochondrial swelling, and nuclear chromatin aggregation. Recent research suggests that oncosis can impact conditions such as chemotherapeutic cardiotoxicity, myocardial ischemic injury, stroke, and cancer, mediated by specific oncosis-related proteins. In this review, we provide a detailed examination of the morphological and molecular features of oncosis and discuss various natural or small molecule compounds that can induce this type of cell death. Additionally, we summarize the current understanding of the molecular mechanisms underlying oncosis and its role in both normal physiology and pathological conditions. These insights aim to illuminate future research directions and propose innovative strategies for leveraging oncosis as a therapeutic tool against human diseases and cancer resistance. Show less
Patients with diabetes have increased risk of cancer and poor response to anti-cancer treatment. Increased protein synthesis is associated with endoplasmic reticulum (ER) stress which can trigger the Show more
Patients with diabetes have increased risk of cancer and poor response to anti-cancer treatment. Increased protein synthesis is associated with endoplasmic reticulum (ER) stress which can trigger the unfolded protein response (UPR) to restore homeostasis, failure of which can lead to dysregulated cellular growth. We hypothesize that hyperglycemia may have legacy effect in promoting survival of cancer cells through dysregulation of UPR. Using HCT116 colorectal cancer cells as a model, we demonstrated the effects of high glucose (25 mM) on promoting cell growth which persisted despite return to normal glucose medium (5.6 mM). Using the Affymetrix gene expression microarray in HCT116 cells programmed by high glucose, we observed activation of genes related to cell proliferation and cell cycle progression and suppression of genes implicated in UPR including BiP and CHOP. These gene expression changes were validated in HCT116 cancer cells using quantitative real-time PCR and Western blot analysis. We further examined the effects of thapsigargin, an anti-cancer prodrug, which utilized ER stress pathway to induce apoptosis. High glucose attenuated thapsigargin-induced UPR and growth inhibition in HCT116 cells, which persisted despite return to normal glucose medium. Western blot analysis showed activation of caspase-3 in thapsigargin-treated cells in both normal and high glucose medium, albeit with lower levels of cleaved caspase-3 in cells exposed to high glucose, suggesting reduced apoptosis. Flow cytometry analysis confirmed fewer apoptotic cells under thapsigargin treatment in cells exposed to high glucose. Our results suggested that hyperglycemia altered gene expression involved in UPR with increased cell proliferation and facilitated survival of HCT116 cells under thapsigargin-induced ER stress by reducing the apoptotic response. Show less