Chemoresistant KM12C Colon Cancer Cells Are Addicted to Low Cyclic AMP Levels in a Phosphodiesterase 4–Regulated Compartment via Effects on Phosphoinositide 3-Kinase

Abstract

One of the major problems in treating colon cancer is chemoresistance to cytotoxic chemotherapeutic agents. There is therefore a need to devise new strategies to inhibit colon cancer cell growth and survival. Here, we show that a combination of low doses of the adenylyl cyclase activator forskolin together with the specific cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) inhibitor rolipram, but not the cAMP phosphodiesterase-3 (PDE3) inhibitor cilostamide, causes profound growth arrest of chemoresistant KM12C colon cancer cells. Low-dose forskolin causes KM12C cells to exit the cell cycle in G 1 by inducing p27Kip1 and primes cells for apoptosis on addition of rolipram. The effect of the low-dose forskolin/ rolipram combination is mediated by displacement of the phosphatidylinositol 3,4,5-trisphosphate/phosphoinositide 3-kinase signaling module from the plasma membrane and suppression of the Akt/protein kinase-B oncogene pathway, to which KM12C cells are addicted for growth. The cAMP and phosphoinositide 3-kinase pathways form a critical intersection in this response, and reexpression of the tumor suppressor lipid phosphatase, phosphatase and tensin homologue, which is commonly lost or mutated in colon cancer, sensitizes KM12C cells to growth inhibition by challenge with low-dose forskolin. Certain chemoresistant colon cancer cells are therefore exquisitely sensitive to subtle elevation of cAMP by a synergistic low-dose adenylyl cyclase activator/PDE4 inhibitor combination. Indeed, these cells are addicted to maintenance of low cAMP concentrations in a compartment that is regulated by PDE4. Well-tolerated doses of PDE4 inhibitors that are already in clinical development for other therapeutic indications may provide an exciting new strategy for the treatment of colon cancer. [Cancer Res 2007;67(11):5248-57]

Triple negative breast cancer development can be selectively suppressed by sustaining an elevated level of cellular cyclic AMP through simultaneously blocking its efflux and decomposition

“…Early studies have reported that agents raising cAMP are able to suppress growth of colon and medullary thyroid cancer cells [32, 33]. However, we found that commonly-used cAMP-elevating agents exhibited little effect on TNBC cell growth (Figure 1).…”

Phosphodiesterase-4 promotes proliferation and angiogenesis of lung cancer by crosstalk with HIF

“…[4][5][6][7] The impairment of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) generation by regulation of phosphodiesterases (PDEs) has been implicated in various cancer pathologies. 8,9 PDEs are enzymes that regulate cellular levels of cAMP/cGMP by controlling their degradation.…”

Loss of phosphodiesterase 4D mediates acquired triapine resistance via Epac-Rap1-Integrin signaling

“…Microdeletions at the PDE4D gene locus in diverse solid tumors resulted in enhanced gene expression and sensitivity towards PDE4D knock-down [43]. Moreover, McEwan et al reported that combination of the PDE4 inhibitor rolipram and low doses of the adenylate cyclase activator forskolin resulted in colon cancer cell growth inhibition implicating that these cells are addicted to maintenance of low cAMP concentrations in a compartment that is regulated by PDE4 [45]. In the present study, deletion of major parts of the PDE4D -coding region as a consequence of triapine selection resulted in almost complete blockade of gene expression at the mRNA and protein level.…”