Expression of cyclic guanosine monophosphate‐dependent protein kinase in metastatic colon carcinoma cells blocks tumor angiogenesis

Kwon, In-Kiu; Schoenlein, Patricia V.; Delk, J.; Liu, Kebin; Thangaraju, Muthusmy; Dulin, Nickolai O.; Ganapathy, Vadivel; Berger, Franklin G.; Browning, Darren D.

doi:10.1002/cncr.23334

Cited by 28 publications

(32 citation statements)

References 29 publications

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“…Surprisingly, the size of the polyps from animals treated with sildenafil did not differ from those from control animals. This result was not anticipated based upon work with human colon cancer cell lines that predicts anti-tumor effects of cGMP signaling that include inhibition of proliferation, increased apoptosis, and inhibition of angiogenesis (9,40,41). Other in vitro studies have demonstrated that cGMP signaling suppresses proliferation without affecting apoptosis, and notably, that it can induce goblet cell differentiation (17,42).…”

Section: Discussionmentioning

confidence: 96%

Sildenafil Suppresses Inflammation-Driven Colorectal Cancer in Mice

Islam

Sharman

Hou

et al. 2017

Cancer Prevention Research

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Intestinal cyclic guanosine monophosphate (cGMP) signaling regulates epithelial homeostasis and has been implicated in the suppression of colitis and colon cancer. In this study, we investigated the cGMP-elevating ability of the phosphodiesterase-5 (PDE5) inhibitor sildenafil to prevent disease in the azoxymethane/dextran sulfate sodium (AOM/DSS) inflammation-driven colorectal cancer model. Treatment of mice with sildenafil activated cGMP signaling in the colon mucosa and protected against DSS-induced barrier dysfunction. In mice treated with AOM/DSS, oral administration of sildenafil throughout the disease course reduced polyp multiplicity by 50% compared to untreated controls. Polyps that did form in sildenafil treated mice were less proliferative and more differentiated compared to polyps from untreated mice, but apoptosis was unaffected. Polyps in sildenafil treated mice were also less inflamed; they exhibited reduced myeloid-cell infiltration, and reduced expression of iNOS, IFNγ, and IL-6 compared to untreated controls. Most of the protection conferred by sildenafil was during the initiation stage of carcinogenesis (38% reduction in multiplicity). Administration of sildenafil during the later promotion stages did not affect multiplicity but had a similar effect on the polyp phenotype, including increased mucus production, and reduced proliferation and inflammation. In summary, the results demonstrate that oral administration of sildenafil suppresses polyp formation and inflammation in mice treated with AOM/DSS. This validation of PDE5 as a target highlights the potential therapeutic value of PDE5 inhibitors for the prevention of colitis-driven colon cancer in humans.

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Section: Discussionmentioning

confidence: 96%

Sildenafil Suppresses Inflammation-Driven Colorectal Cancer in Mice

Islam

Sharman

Hou

et al. 2017

Cancer Prevention Research

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“…Expression of PKG-I is downregulated in multiple tumor tissues compared with respective normal tissues (26). Activation of cGMP/PKG pathway inhibits breast or colon cancer cell growth and angiogenesis, and it induces these cells' apoptosis (13,27,47). A death-associated protein kinase 2 has been identified to be the substrate of PKG-I and mediates PKG-Iinduced breast cancer cell apoptosis (25).…”

Section: Discussionmentioning

confidence: 98%

“…Previous studies suggested that PKG may be proapoptotic or anti-apoptotic, depending on cell types (19, 50). Recently, a proapoptotic role of PKG has been shown in various cancer cell types, linking cGMP/PKG signaling to anti-tumor activities (13,15,16,27,47). Expression of PKG-I is downregulated in multiple tumor tissues compared with respective normal tissues (26).…”

Section: Discussionmentioning

confidence: 98%

“…In addition to regulating vessel wall function, our previous studies demonstrate a renal protective effect of PKG-I activation on diabetes or ischemia-reperfusion-induced kidney injury (29,52). Recently, numerous studies suggest an anti-tumor effect of cGMP/PKG signaling, including induction of tumor cell apoptosis and inhibition of metastasis (13,15,16,27,47). Moreover, expression of PKG-I is reduced in many tumors compared with normal tissues (26).…”

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confidence: 94%

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Increasing cGMP-dependent protein kinase I activity attenuates cisplatin-induced kidney injury through protection of mitochondria function

Maimaitiyiming

Cui

et al. 2013

American Journal of Physiology-Renal Physiology

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Cisplatin is widely used to treat malignancies. However, its major limitation is the development of dose-dependent nephrotoxicity. The precise mechanisms of cisplatin-induced kidney damage remain unclear, and the renoprotective agents during cisplatin treatment are still lacking. Here, we demonstrated that the expression and activity of cGMP-dependent protein kinase-I (PKG-I) were reduced in cisplatin-treated renal tubular cells in vitro as well as in the kidney tissues from cisplatin-treated mice in vivo. Increasing PKG activity by both pharmacological and genetic approaches attenuated cisplatin-induced kidney cell apoptosis in vitro. This was accompanied by decreased Bax/Bcl2 ratio, caspase 3 activity, and cytochrome c release. Cisplatin-induced mitochondria membrane potential loss in the tubular cells was also prevented by increased PKG activity. All of these data suggest a protective effect of PKG on mitochondria function in renal tubular cells. Importantly, increasing PKG activity pharmacologically or genetically diminished cisplatin-induced tubular damage and preserved renal function during cisplatin treatment in vivo. Mitochondria structural and functional damage in the kidney from cisplatin-treated mice was inhibited by increased PKG activity. In addition, increasing PKG activity enhanced ciaplatin-induced cell death in several cancer cell lines. Taken together, these results suggest that increasing PKG activity may be a novel option for renoprotection during cisplatin-based chemotherapy.

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“…The expression of PKG1 is reduced in colon tumors relative to matched normal tissue and is barely detectable in colon cancer cell lines (13). Ectopic reexpression of PKG1 in colon cancer cells blocks xenograft growth (13,17), presumably by inhibiting ␤-catenin/TCF (19) and hypoxia signaling (18). PKG2 expression is not reduced in colon tumors (not shown) but was not detected in any of the colon cancer cell lines examined in the present study.…”

Section: Discussionmentioning

confidence: 99%

Type 2 cGMP-dependent protein kinase regulates proliferation and differentiation in the colonic mucosa

Wang

Kwon

Thangaraju

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Signaling through cGMP has emerged as an important regulator of tissue homeostasis in the gastrointestinal tract, but the mechanism is not known. Type 2 cGMP-dependent protein kinase (PKG2) is a major cGMP effector in the gut epithelium, and the present studies have tested its importance in the regulation of proliferation and differentiation in the mouse colon and in colon cancer cell lines. Tissue homeostasis was examined in the proximal colon of Prkg2(-/-) mice using histological markers of proliferation and differentiation. The effect of ectopic PKG2 on proliferation and differentiation was tested in vitro using inducible colon cancer cell lines. PCR and luciferase reporter assays were used to determine the importance of Sox9 downstream of PKG2. The colons of Prkg2(-/-) mice exhibited crypt hyperplasia, increased epithelial apoptosis, and reduced numbers of differentiated goblet and enteroendocrine cells. Ectopic PKG2 was able to inhibit proliferation and induce Muc2 and CDX2 expression in colon cancer cells, but did not significantly affect cell death. PKG2 reduced Sox9 levels and signaling, suggesting possible involvement of this pathway downstream of cGMP in the colon. The work presented here demonstrates a novel antiproliferative and prodifferentiation role for PKG2 in the colon. These homeostatic functions of PKG2 were reproducible in colon cancer cells lines where downregulation of Sox9 is a possible mechanism. The similarities in phenotype between PKG2 and GCC knockout mice positions PKG2 as a likely mediator of the homeostatic effects of cGMP signaling in the colon.

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Expression of cyclic guanosine monophosphate‐dependent protein kinase in metastatic colon carcinoma cells blocks tumor angiogenesis

Cited by 28 publications

References 29 publications

Sildenafil Suppresses Inflammation-Driven Colorectal Cancer in Mice

Sildenafil Suppresses Inflammation-Driven Colorectal Cancer in Mice

Increasing cGMP-dependent protein kinase I activity attenuates cisplatin-induced kidney injury through protection of mitochondria function

Type 2 cGMP-dependent protein kinase regulates proliferation and differentiation in the colonic mucosa

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