A novel MTORC2-AKT-ROS axis triggers mitofission and mitophagy-associated execution of colorectal cancer cells upon drug-induced activation of mutant KRAS.

RAS is one of the most commonly mutated oncogenes associated with multiple cancer hallmarks. Notably, RAS activation induces intracellular reactive oxygen species (ROS) generation, which we previously demonstrated as a trigger for autophagy-associated execution of mutant KRAS-expressing cancer cells. Here we report that drug (merodantoin; C1)-induced activation of mutant KRAS promotes phospho-AKT S473-dependent ROS-mediated S616 phosphorylation and mitochondrial localization of DNM1L/DRP1 (dynamin 1 like) and cleavage of the fusion-associated protein OPA1 (OPA1 mitochondrial dynamin like GTPase).

Therapeutic Potential of a Senolytic Approach in a Murine Model of Chronic GVHD.

Graft-versus-host disease (GVHD) is a life-threatening systemic complication of allogeneic hematopoietic stem cell transplantation (HSCT) characterized by dysregulation of T and B cell activation and function, scleroderma-like features, and multi-organ pathology. The treatment of cGVHD is limited to the management of symptoms and long-term use of immunosuppressive therapy, which underscores the need for developing novel treatment approaches. Notably, there is a striking similarity between cytokines/chemokines responsible for multi-organ damage in cGVHD and pro-inflammatory factors, immune modulators, and growth factors secreted by senescent cells upon the acquisition of senescence-associated secretory phenotype (SASP).

TRAIL sensitivity of nasopharyngeal cancer cells involves redox dependent upregulation of TMTC2 and its interaction with membrane caspase-3.

Aims: Preferential expression of receptors for TNF-family related apoptosis inducing ligand (TRAIL), DR4 and DR5 makes TRAIL an attractive anti-cancer therapeutic. However, the efficacy of targeting death receptors has not been extensively studied in nasopharyngeal cancer (NPC). Here we investigated TRAIL sensitivity and its underlying mechanism in NPC cell lines, and assessed the potential of TRAIL as a therapeutic option against NPC.

Serine-70 phosphorylated Bcl-2 prevents oxidative stress-induced DNA damage by modulating the mitochondrial redox metabolism.

Bcl-2 phosphorylation at serine-70 (S70pBcl2) confers resistance against drug-induced apoptosis. Nevertheless, its specific mechanism in driving drug-resistance remains unclear. We present evidence that S70pBcl2 promotes cancer cell survival by acting as a redox sensor and modulator to prevent oxidative stress-induced DNA damage and execution.

Peroxynitrite promotes serine-62 phosphorylation-dependent stabilization of the oncoprotein c-Myc.

Stabilization of c-Myc oncoprotein is dependent on post-translational modifications, especially its phosphorylation at serine-62 (S62), which enhances its tumorigenic potential. Herein we report that increase in intracellular superoxide induces phospho-stabilization and activation of c-Myc in cancer cells. Importantly, sustained phospho-S62 c-Myc was necessary for promoting superoxide dependent chemoresistance as non-phosphorylatable S62A c-Myc was insensitive to the redox impact when subjected to chemotherapeutic insults.

Redox inhibition of protein phosphatase PP2A: Potential implications in oncogenesis and its progression.

Cellular processes are dictated by the active signaling of proteins relaying messages to regulate cell proliferation, apoptosis, signal transduction and cell communications. An intricate web of protein kinases and phosphatases are critical to the proper transmission of signals across such cascades. By governing 30-50% of all protein dephosphorylation in the cell, with prominent substrate proteins being key regulators of signaling cascades, the phosphatase PP2A has emerged as a celebrated player in various developmental and tumorigenic pathways, thereby posing as an attractive target for therapeutic intervention in various pathologies wherein its activity is deregulated.

Breast Cancer: A Molecular and Redox Snapshot.

Significance: Breast cancer is a unique disease characterized by heterogeneous cell populations causing roadblocks in therapeutic medicine, owing to its complex etiology and primeval understanding of the biology behind its genesis, progression, and sustenance. Globocan statistics indicate over 1.7 million new breast cancer diagnoses in 2012, accounting for 25% of all cancer morbidities.