Cellular Redox: A Modulator of Intestinal Epithelial Cell Proliferation
The current review will focus on the concepts salient to understanding control of cellular redox homeostasis, the relationship between cellular redox and cell proliferation, and how a loss of this redox balance alters intestinal cell proliferative responses. This knowledge underpins the centrality of cellular redox in governing cell growth.
Glutathione and thiol redox balance.
The tripeptide glutathione (known as γ-glutamylcysteinylglycine or GSH) is the major low-molecular-weight thiol in cells that controls cellular thiol-disulfide redox state, which is essential for normal redox signaling (9). The dynamics of cellular redox balance are achieved by maintenance of the thiol-to-disulfide status of reduced GSH and its oxidized form, GSSG. Oxidation-reduction and thiol-disulfide exchange reactions during oxidative perturbations will cause a redistribution of GSH and GSSG; the resultant quantitative shift in the ratio of GSH to GSSG in favor of GSSG directly reflects an oxidized redox status and is a convenient expression of oxidative stress within a cell. The redox potential (Eh), which takes into consideration the stoichiometry of two GSH oxidized per GSSG formed, is another useful quantitative expression for the redox state of the GSH/GSSG pool. Eh is calculated by the Nernst equation: Eh = Eo + (RT/nF)ln([GSSG]/[GSH]2) (9) (where Eo is the standard potential for the redox couple at defined pH, R is the gas constant, T is the absolute temperature, F is Faraday’s constant, and n is the number of electrons transferred), and cellular estimates of Eh for the GSH/GSSG redox couple are in the range of −260 to −200 mV. During oxidative stress, intracellular GSSG accumulates (Fig. 1⇓), and the loss of thiol redox balance will elicit deleterious consequences for metabolic regulation, cellular integrity, and organ homeostasis. The regulation of intestinal thiol redox balance is a complex process, and apart from the GSH/GSSG couple, the cysteine/cysteine redox redox pair is also an important contributor to control of intestinal thiol/disulfide balance.
Redox status governs differential cell transition to proliferative or apoptotic states.
The fate of cells in multicellular organisms is decided by survival or promoting signals. Whereas survival signals mediate cell maintenance through influencing metabolic events, promoting signals direct targeted cells toward proliferation, differentiation, transformation, or death by apoptosis. Fully differentiated tissues like the liver, kidney, brain, and intestine are characterized by cells arrested in the quiescent state, and imposition of severe oxidative stress often results in a cytotoxic biological endpoint. However, necrotic death is not necessarily an obligatory endpoint of all oxidative stress. Indeed, subtoxic oxidative stress and mild redox shifts can induce transition of a cell from a quiescent state to that of a proliferative or apoptotic state. Prevailing evidence shows that shifting control checkpoints in the direction of reduction or oxidation (i.e., to a relatively more negative or positive Eh, respectively) results in a cell that favors quiescence, proliferation, growth arrest, differentiation, or apoptosis (Ref. 2; Fig. 2⇓). Terminally quiescent cells like hepatocytes exhibit a biological constraint to proliferate due to a mitotic block (Fig. 2⇓, curve I). An elevation in oxidation toward a more positive Eh induces cell progression to growth arrest, differentiation, or death by apoptosis. A genetic program in mitotically competent cells signals cell proliferation in response to an antigenic, mitogenic, or redox stimulus (Fig. 2⇓, curve II). These initial stimuli may provide the “priming” event that lowers the barrier of cell cycle regulatory checkpoints (e.g., G0/G1 transition) that subsequently drive the cell to proliferate. Intestinal cells, because of their high turnover rate, represent such a cell type wherein subtoxic oxidant challenge causes a sufficient oxidative shift in the cellular redox that allows for enhanced mitogenic response. Whereas transformed or tumor cells normally exhibit few barriers to proliferation, a subtoxic oxidant dose with the associated mild redox shift could provide a stimulus for further growth potential or push the cell beyond the maximal point of damage that initiates the apoptotic phase (Fig. 2⇓, curve III). Anticancer drugs are known principally to operate by “forcing” actively proliferating tumor cells into apoptosis (10); whether cellular redox mediates this cell transition is unclear. Collectively, these examples illustrate the fundamental concept that cellular responses to oxidative stress and redox imbalance are not linear but are bell-shaped, and, depending on the severity of redox shift, proliferation, differentiation, or apoptosis may predominate.
