11-cis-retinal and Cell-Transformation--Neoplastic

Protease-activated receptors (PARs) are G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. Besides the important role of blood coagulation factors in preventing bleeding after vascular injury, these serine proteinases actively engage target cells thereby fulfilling critical functions in cell biology. Cellular responses triggered by coagulation factor-induced PAR activation suggest that PARs play an important role in proliferation, survival and/or malignant transformation of tumor cells. Indeed, PAR expression correlates with cancer malignancy and clinical studies show that anticoagulant treatment is beneficial in cancer patients. In this review, we provide an overview on the PAR family, their mode of activation and mechanisms by which PAR signaling is terminated. In addition, we discuss the relationship between blood coagulation and cancer biology focusing on the potential role of PAR-induced modulation of cell survival, apoptosis and tumor growth.

Topics: Amino Acid Sequence; Animals; Apoptosis; Blood Coagulation Factors; Caspases; Cell Division; Cell Transformation, Neoplastic; Conserved Sequence; Enzyme Activation; Heterotrimeric GTP-Binding Proteins; Humans; Mice; Mice, Knockout; Models, Molecular; Molecular Sequence Data; Neoplasm Proteins; Neoplasms; Protein Conformation; Protein Structure, Tertiary; Receptors, Proteinase-Activated; Rhodopsin; Sequence Alignment; Sequence Homology, Amino Acid; Signal Transduction; Thrombophilia; Thromboplastin

It has long been known that the resting potential of tumor cells is depolarized relative to their normal counterparts. More recent work has provided evidence that resting potential is not just a readout of cell state: it regulates cell behavior as well. Thus, the ability to control resting potential in vivo would provide a powerful new tool for the study and treatment of tumors, a tool capable of revealing living-state physiological information impossible to obtain using molecular tools applied to isolated cell components. Here we describe the first use of optogenetics to manipulate ion-flux mediated regulation of membrane potential specifically to prevent and cause regression of oncogene-induced tumors. Injection of mutant-KRAS mRNA induces tumor-like structures with many documented similarities to tumors, in Xenopus tadpoles. We show that expression and activation of either ChR2D156A, a blue-light activated cation channel, or Arch, a green-light activated proton pump, both of which hyperpolarize cells, significantly lowers the incidence of KRAS tumor formation. Excitingly, we also demonstrate that activation of co-expressed light-activated ion translocators after tumor formation significantly increases the frequency with which the tumors regress in a process called normalization. These data demonstrate an optogenetic approach to dissect the biophysics of cancer. Moreover, they provide proof-of-principle for a novel class of interventions, directed at regulating cell state by targeting physiological regulators that can over-ride the presence of mutations.

Topics: Animals; Antineoplastic Agents; Archaeal Proteins; Cell Transformation, Neoplastic; Embryo, Nonmammalian; Humans; Light; Membrane Potentials; Mutation; Optogenetics; Proto-Oncogene Proteins p21(ras); Rhodopsin; RNA, Messenger; Xenopus laevis