The role of infections in the causation of cancer in Kenya.

Cancer constitutes a major health care burden in the world today with the situation worsening in resource poor settings as seen in most Sub-Saharan African (SSA) countries. Infections constitute by far the most common risk factors for cancer in SSA and being a typical country in this region, Kenya has experienced an upsurge in the incidence of various types of cancers in the last few decades. Although there is limited population-based data in Kenya of infections-associated cancers, this review provides an up-to-date literature-based discussion on infections-associated cancers, their pathogenesis, and preventive approaches in the country. The primary infectious agents identified are largely viral (human immunodeficiency virus, human papillomavirus (HPV), Kaposi's sarcoma-associated herpes virus, Epstein-Barr virus, hepatitis B virus (HBV), hepatitis C virus), and also bacterial: Helicobacter pylori and parasitic: Schistosomiasis haematobium. Cancers associated with infections in Kenya are varied but the predominant ones are Non-Hodgkin lymphoma, Kaposi's sarcoma, Hodgkin lymphoma, Burkitt's lymphoma, cervical, liver, and gastric cancers. The mechanisms of infections-induced carcinogenesis are varied but they mainly seem to stem from disruption of signaling, chronic inflammation, and immunosuppression. Based on our findings, actionable cancer-preventive measures that are economically feasible and aligned with existing infrastructure in Kenya include screening and treatment of infections, implementation of cancer awareness and screening, and vaccination against infections primarily HBV and HPV. The development of vaccines against other infectious agents associated with causation of cancer remains also as an important goal in cancer prevention.

A clickable glutathione approach for identification of protein glutathionylation in response to glucose metabolism.

Glucose metabolism and mitochondrial function are closely interconnected with cellular redox-homeostasis. Although glucose starvation, which mimics ischemic conditions or insufficient vascularization, is known to perturb redox-homeostasis, global and individual protein glutathionylation in response to glucose metabolism or mitochondrial activity remains largely unknown. In this report, we use our clickable glutathione approach, which forms clickable glutathione (azido-glutathione) by using a mutant of glutathione synthetase (GS M4), for detection and identification of protein glutathionylation in response to glucose starvation. We found that protein glutathionylation is readily induced in HEK293 cells in response to low glucose concentrations when mitochondrial reactive oxygen species (ROS) are elevated in cells, and glucose is the major determinant for inducing reversible glutathionylation. Proteomic and biochemical analysis identified over 1300 proteins, including SMYD2, PP2Cα, and catalase. We further showed that PP2Cα is glutathionylated at C314 in a C-terminal domain, and PP2Cα C314 glutathionylation disrupts the interaction with mGluR3, an important glutamate receptor associated with synaptic plasticity.

Carbohydrate-based inducers of cellular stress for targeting cancer cells.

Small molecules that block the altered metabolism in cancer or increase the production of reactive oxygen species (ROS) are emerging as potential anti-cancer agents. Considering that various carbohydrates can be used for cellular energetics or protein N-glycosylation of which interruption can lead to cellular stress, we have synthesized and evaluated a library of N-aryl glycosides for induction of ROS and cytotoxicity in H1299 cancer cell line. Two N-aryl glycosides (K8 and H8) were identified that induce about 2-fold induction of ROS and cytotoxicity in H1299 cells. We further showed that the acetylated form of K8 (K8A) activates AMPK, and stabilizes p53 in HEK293 cells, and induce a higher cytotoxicity than 2-deoxy-d-glucose in H1299 cell line.