Tumor Signaling and Angiogenesis


The Browning laboratory seeks to exploit cGMP signaling in the colon mucosa for the treatment of inflammatory bowel disease and the prevention of colon cancer.

Type 2 cGMP-dependent protein kinase was shown to regulate homeostasis by blocking c-Jun N-terminal kinase in the colon epithelium (Cell Death Dif fer.2014, 21:427-437). This work describes the first evidence to directly demonstrate that activation of cGMP signaling in the colon epithelium of normal (wild-type) mice is barrier-protective. More importantly, they showed that clinically available erectile dysfunction drugs are able to activate this pathway and could block experimental colitis in mice. The mechanism was shown to involve PKG2-dependent inhibition of stress signaling through the JNK pathway. Using VIAGRA® (sildenafil citrate) in mice, the laboratory continues to build upon previous finding that cGMP/PKG2 activation by erectile dysfunction drugs can protect the lining of the colon from damage. They have demonstrated that cGMP/PKG2 can activate the tumor-suppressor protein FoxO3a. This transcription factor activates protective antioxidant gene expression, and it was shown that cGMP signaling protects the colon epithelium from oxidative damage.

Bardhan K, Paschall AV, Yang D, Chen MR, Simon PS, Bhutia YD, Martin PM, Thangaraju M, Browning DD, Ganapathy V, Heaton CM, Gu K, Lee JR, Liu K. IFNγ Induces DNA Methylation-Silenced GPR109A Expression via pSTAT1/p300 and H3K18 Acetylation in Colon Cancer. Cancer Immunol Res. 2015 Jul;3(7):795-805. doi: 10.1158/2326-6066.CIR-14-0164. Epub 2015 Mar 3. PMID: 25735954

Wang R, Kwon IK, Thangaraju M, Singh N, Liu K, Jay P, Hofmann F, Ganapathy V, Browning DD. Type 2 cGMP-dependent protein kinase regulates proliferation and differentiation in the colonic mucosa. Am J Physiol Gastrointest Liver Physiol. 2012 Jul 15;303(2):G209-19. doi: 10.1152/ajpgi.00500.2011. Epub 2012 May 3. PMID: 22556146

Elangovan S, Ramachandran S, Venkatesan N, Ananth S, Gnana-Prakasam JP, Martin PM, Browning DD, Schoenlein PV, Prasad PD, Ganapathy V, Thangaraju M. SIRT1 is essential for oncogenic signaling by estrogen/estrogen receptor α in breast cancer. Cancer Res. 2011 Nov 1;71(21):6654-64. doi: 10.1158/0008-5472.CAN-11-1446. Epub 2011 Sep 15. PMID: 21920899

Kwon IK, Wang R, Prakash N, Bozard R, Baudino TA, Liu K, Thangaraju M, Dong Z, Browning DD. Cyclic 3',5'-guanosine monophosphate-dependent protein kinase inhibits colon cancer cell adaptation to hypoxia. Cancer. 2011 Dec 1;117(23):5282-93. doi: 10.1002/cncr.26192. Epub 2011 May 11. PMID: 21563174

Browning DD, Kwon IK, Wang R. cGMP-dependent protein kinases as potential targets for colon cancer prevention and treatment. Future Med Chem. 2010 Jan;2(1):65-80. doi: 10.4155/fmc.09.142. Review. PMID: 21426046

Zhu S, Browning DD, White RE, Fulton D, Barman SA. Mutation of protein kinase C phosphorylation site S1076 on alpha-subunits affects BK(Ca) channel activity in HEK-293 cells. Am J Physiol Lung Cell Mol Physiol. 2009 Oct;297(4):L758-66. doi: 10.1152/ajplung.90518.2008. Epub 2009 Jul 10. PMID: 19592459

Thangaraju M, Cresci GA, Liu K, Ananth S, Gnanaprakasam JP, Browning DD, Mellinger JD, Smith SB, Digby GJ, Lambert NA, Prasad PD, Ganapathy V. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res. 2009 Apr 1;69(7):2826-32. doi: 10.1158/0008-5472.CAN-08-4466. Epub 2009 Mar 10. PMID: 19276343

Thangaraju M, Cresci G, Itagaki S, Mellinger J, Browning DD, Berger FG, Prasad PD, Ganapathy V. Sodium-coupled transport of the short chain fatty acid butyrate by SLC5A8 and its relevance to colon cancer. J Gastrointest Surg. 2008 Oct;12(10):1773-81; discussion 1781-2. doi: 10.1007/s11605-008-0573-0. Epub 2008 Jul 26. PMID: 18661192

Browning DD. Protein kinase G as a therapeutic target for the treatment of metastatic colorectal cancer. Expert Opin Ther Targets. 2008 Mar;12(3):367-76. doi: 10.1517/14728222.12.3.367. Review. PMID: 18269345

Kwon IK, Schoenlein PV, Delk J, Liu K, Thangaraju M, Dulin NO, Ganapathy V, Berger FG, Browning DD. Expression of cyclic guanosine monophosphate-dependent protein kinase in metastatic colon carcinoma cells blocks tumor angiogenesis. Cancer. 2008 Apr 1;112(7):1462-70. doi: 10.1002/cncr.23334. PMID: 18260092

Ying L, Hofseth AB, Browning DD, Nagarkatti M, Nagarkatti PS, Hofseth LJ. Nitric oxide inactivates the retinoblastoma pathway in chronic inflammation. Cancer Res. 2007 Oct 1;67(19):9286-93. PMID: 17909036

Yang D, Thangaraju M, Browning DD, Dong Z, Korchin B, Lev DC, Ganapathy V, Liu K. IFN regulatory factor 8 mediates apoptosis in nonhemopoietic tumor cells via regulation of Fas expression. J Immunol. 2007 Oct 1;179(7):4775-82. PMID: 17878376

Yang D, Ud Din N, Browning DD, Abrams SI, Liu K. Targeting lymphotoxin beta receptor with tumor-specific T lymphocytes for tumor regression. Clin Cancer Res. 2007 Sep 1;13(17):5202-10. PMID: 17785576

Burgoyne JR, Madhani M, Cuello F, Charles RL, Brennan JP, Schröder E, Browning DD, Eaton P. Cysteine redox sensor in PKGIa enables oxidant-induced activation. Science. 2007 Sep 7;317(5843):1393-7. Epub 2007 Aug 23. PMID: 17717153

Barnes IH, Bagnall MC, Browning DD, Thompson SA, Manning G, Newell DG. Gamma-glutamyl transpeptidase has a role in the persistent colonization of the avian gut by Campylobacter jejuni. Microb Pathog. 2007 Nov-Dec;43(5-6):198-207. Epub 2007 May 21. PMID: 17600669

Godfrey EW, Longacher M, Neiswender H, Schwarte RC, Browning DD. Guanylate cyclase and cyclic GMP-dependent protein kinase regulate agrin signaling at the developing neuromuscular junction. Dev Biol. 2007 Jul 15;307(2):195-201. Epub 2007 Apr 24. PMID: 17560564

Yang D, Thangaraju M, Greeneltch K, Browning DD, Schoenlein PV, Tamura T, Ozato K, Ganapathy V, Abrams SI, Liu K. Repression of IFN regulatory factor 8 by DNA methylation is a molecular determinant of apoptotic resistance and metastatic phenotype in metastatic tumor cells. Cancer Res. 2007 Apr 1;67(7):3301-9. PMID: 17409439

Hou Y, Wong E, Martin J, Schoenlein PV, Dostmann WR, Browning DD. A role for cyclic-GMP dependent protein kinase in anoikis. Cell Signal. 2006 Jun;18(6):882-8. Epub 2005 Aug 31. PMID: 16139477

Hou Y, Ye RD, Browning DD. Activation of the small GTPase Rac1 by cGMP-dependent protein kinase. Cell Signal. 2004 Sep;16(9):1061-9. PMID: 15212766

Marty C, Browning DD, Ye RD. Identification of tetratricopeptide repeat 1 as an adaptor protein that interacts with heterotrimeric G proteins and the small GTPase Ras. Mol Cell Biol. 2003 Jun;23(11):3847-58. PMID: 12748287

Hou Y, Lascola J, Dulin NO, Ye RD, Browning DD. Activation of cGMP-dependent protein kinase by protein kinase C. J Biol Chem. 2003 May 9;278(19):16706-12. Epub 2003 Feb 27. PMID: 12609995