Exisulind and guanylyl cyclase C induce distinct antineoplastic signaling mechanisms in human colon cancer cells

Abstract

The nonsteroidal anti-inflammatory drug sulindac is metabolized to sulindac sulfone (exisulind), an antineoplastic agent that inhibits growth and induces apoptosis in solid tumors. In colon cancer cells, the antineoplastic effects of exisulind have been attributed, in part, to induction of cyclic guanosine 3 ¶,5 ¶-monophosphate (cGMP) signaling through inhibition of cGMP-specific phosphodiesterases, which elevates intracellular cGMP, and novel expression of cGMP-dependent protein kinase (PKG) IB, the presumed downstream effector mediating apoptosis. Here, inhibition of proliferation and induction of cell death by exisulind was dissociated from cGMP signaling in human colon cancer cells. Accumulation of intracellular cGMP produced by an exogenous cell-permeant analogue of cGMP or a potent agonist of guanylyl cyclase C yielded cytostasis without cell death. Surprisingly, the antiproliferative effects of induced cGMP accumulation were paradoxically less than additive, rather than synergistic, when combined with exisulind. Further, although exisulind induced expression of PKG IB, it did not elevate intracellular cGMP and its efficacy was not altered by inhibition or activation of PKG I. Rather, PKG I induced by exisulind may mediate desensitization of cytostasis induced by cGMP. Thus, cytotoxic effects of exisulind are independent of cGMP signaling in human colon cancer cells. Moreover, combination therapies, including exisulind and agents that induce cGMP signaling, may require careful evaluation in patients with colon cancer.

Homeostatic Control of the Crypt-Villus Axis by the Bacterial Enterotoxin Receptor Guanylyl Cyclase C Restricts the Proliferating Compartment in Intestine

“…Indeed, the colonic crypts of Lieberkuhn include the entire cell phenotypic spectrum along the crypt-villus axis, whereas shorter small intestinal crypts ( Figure 1H), apically restricted by the cryptvillus junction (Figure 8), are predominantly populated by proliferating progenitor cells ( Figure 2B). In agreement with the suggestion that GC-C critically regulates cell proliferative dynamics, induction of GC-C signaling using ST or 8-br-cGMP, a membrane-permeant cGMP analog, 30 inhibited proliferation of normal epithelial cells in mucosal sheets isolated from intestines of patients, as assessed by 3 H-thymidine incorporation into nuclear DNA ( Figure 3A). Further, ST or the endogenous GC-C agonist guanylin, but not the inactive ST analog TJU 1-103, inhibited proliferation of NCM460 human intestinal crypt cells 22 ( Figure 3B), and this effect was mimicked by 8-br-cGMP ( Figure 3C).…”

“…4,6,8 Moreover, dysregulated GC-C signaling reflecting loss of ligands eliminates one important cytostatic mechanism inhibiting proliferation in transformed cells, potentiating tumor promotion. [11][12][13]30 Of significance, loss of guanylin and uroguanylin expression in human tumors is associated with near-uniform overexpression of GC-C, 23,27 suggesting paracrine hormone replacement therapy as a novel chemopreventive strategy to maintain crypt-villus homeostasis and suppress tumor initiation and promotion in intestine. 38 …”

Cyclic GMP induced apoptosis via protein kinase G in oestrogen receptor‐positive and ‐negative breast cancer cell lines

“…Discussion cGMP mediates discrete cellular functions in mammalian cells by interacting with target proteins, including PKG, cyclic nucleotide-gated channels and specific phosphodiesterases [8][9][10]. There is increasing evidence that activation of the cGMP ⁄ PKG pathway can play an important role in the inhibition of cell proliferation and induction of apoptosis in cancer cells [18][19][20][21][22][23]. Recently, a cDNA array was performed to study PKGI mRNA levels in several tumor types.…”

Interlude of cGMP and cGMP/Protein Kinase G Type 1 in Pancreatic Adenocarcinoma Cells

“…The expression of PKG1 has been documented for colon cancer cells, 15 ovarian cancer cells, 7,16 and recently, nonsmall cell lung cancer cells. 17 The PKG2 expression has been found in gastric cancer cells.…”