Expression of p27(Kip1), a Cyclin-Dependent Kinase Inhibitor, in Human Peripheral Blood Mononuclear Cells Is Inversely Associated with Potential Carcinogenic Risk in Obese Type 2 Diabetic Individuals Relative to Lean Normal Controls

Isao Eto

Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, USA.

DOI: 10.4236/ajmb.2014.43013                

Abstract

Introduction: The consensus report issued jointly by the American Diabetes Association and the American Cancer Society stated that “type 2 diabetes and cancer share many risk factors, but potential biologic links between the two diseases are incompletely understood”. Interestingly, however, a recent report suggested that the expression of p27(Kip1), a cell cycle repressor protein, in the rodent liver was inversely associated with potential carcinogenic risk in the genetic rodent models of diabetic obesity. p27 is a cyclin-dependent kinase inhibitor that, when down-regulated, allows the progression of the cell cycle from G1 to S phase, thereby increasing the risk of developing cancer. Objective: The objective of the study described below was to extend the results of the recent report on the expression of p27 in the livers of obese, diabetic rodents to the humans and investigate whether the expression of p27 in the human peripheral blood mononuclear cells (PBMCs) might also be inversely associated with potential carcinogenic risk in obese type 2 diabetic individuals relative to the lean normal controls. Methods: Western immunoblot analysis was performed to evaluate the expression of p27 and the two most relevant upstream molecular signaling pathways of the expression of p27, namely 4E-BP1 and MNK1, in human PBMCs obtained from obese type 2 diabetic individuals relative to the lean normal controls. Results: First, expression of p27 in human PBMCs was significantly down-regulated in obese type 2 diabetic individuals relative to the lean normal controls. Secondly, expression of p27 in human PBMCs was also significantly down-regulated in obese type 2 diabetic African Americans relative even to the obese type 2 diabetic Caucasian Americans. Conclusions: Expression of p27 in human PBMCs was inversely associated with potential carcinogenic risk in obese type 2 diabetes relative to the lean normal controls.

Keywords

Zucker Rats, Liver, Kidney, Diabetic Nephropathy, 4E-BP1, MNK1, eIF4E

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Giovannucci, E., Harlan, D.M., Archer, M.C., Bergenstal, R.M., Gapstur, S.M., Habel, L.A., Pollak, M., Regensteiner, J.G. and Yee, D. (2010) Diabetes and Cancer: A Consensus Report. Diabetes Care, 33, 1674-1685. http://dx.doi.org/10.2337/dc10-0666
[2]	Eto, I. (2013) Expression of p27Kip1, A Cell Cycle Repressor Protein, Is Inversely Associated with Potential Carcinogenic Risk in the Genetic Rodent Models of Obesity and Long-Lived Ames Dwarf Mice. Metabolism, 62, 873-888. http://dx.doi.org/10.1016/j.metabol.2013.01.001
[3]	Hakkak, R., Holley, A.W., Bunn, R.C., Winters, A. and MacLeod, S. (2005) Effects of Obesity on Serum Insulin Growth Factor 1 (IGF-1) Levels in Lean and Obese Female Zucker Rats Following DMBA Treatment. The FASEB Journal-Proceedings, 19, A993.
[4]	Hakkak, R., Holley, A.W., Gnoand, F. and Owens, R. (2005) Effects of Obesity on Serum Adiponectin Levels and Breast Cancer Development in Lean and Obese Female Zucker Rats Following DMBA Ttreatment. The FASEB Journal-Proceedings, 19, A993.
[5]	Hakkak, R., Holley, A.W., MacLeod, S., Simpson, P. and Korourian, P. (2005) Obesity Promotes DMBA Induced Mammary Tumor Development in Female Zucker Rats. The FASEB Journal-Proceedings, 19, A774.
[6]	Hakkak, R., Holley, A.W., MacLeod, S., Simpson, P., Fuchs, G., Jo, C.H., Kieber-Emmons, T. and Korourian, S. (2005) Obesity Promotes7,12-Dimethylbenz(a)anthracene-Induced Mammary Tumor Development in Female Zucker Rats. Breast Cancer Research, 7, R627-R633. http://dx.doi.org/10.1186/bcr1263
[7]	Hakkak, R., Shaaf, S., Jo, C.H., MacLeod, S. and Korourian, S. (2010) Dehydroepiandrosterone Intake Protects against 7,12-Dimethylbenz(a)anthracene-Induced Mammary Tumor Development in the Obese Zucker Rat Model. Oncology Report, 24, 357-362. http://dx.doi.org/10.3892/or_00000867
[8]	Hakkak R., MacLeod, S., Shaaf, S., Holley, A. W., Simpson, P., Fuchs, G., Jo, C.H., Kieber-Emmons, T. and Korourian, S. (2007) Obesity Increases the Incidence of 7,12-Dimethylbenz(a)anthracene-Induced Mammary Tumors in Ovariectomized Zucker Rat. International Journal of Oncology, 30, 557-563.
[9]	Whitehead, T., Holley, A.W., Kieber-Emmons, T., Korourian, S. and Hakkak, R. (2005) Metabolic Phenotype of the DMBA-induced Mammary Tumor in Obese Female Zucker Rats. Proceedings of the American Association for Cancer Research, 46, 6074.
[10]	Ikeno, Y., Bronson, R.T., Hubbard, G.B., Lee, S. and Bartke, A. (2003) Delayed Occurrence of Fatal Neoplastic Diseases in Ames Dwarf Mice: Correlation to Extended Longevity. Journal of Gerontology Series A, 58, B291-B296. http://dx.doi.org/10.1093/gerona/58.4.B291
[11]	Sharp, Z.D. and Bartke, A. (2005) Evidence for Down-Regulation of Phosphoinositide 3-Kinase/Akt/Mammalian Target of Rapamycin (PI3K/Akt/mTOR)-Dependent Translation Regulatory Signaling Pathways in Ames Dwarf Mice. Journal of Gerontology Series A, 60, 293-300.
[12]	Eto, I. (2006) Nutritional and Chemopreventive Anti-Cancer Agents Up-Regulate Expression of p27Kip1, A Cyclin-Dependent Kinase Inhibitor, in Mouse JB6 Epidermal and Human MCF7, MDAMB-321 and AU565 Breast Cancer Cells. Cancer Cell International, 6, 1-19. http://www.cancerci.com/content/6/1/20 http://dx.doi.org/10.1186/1475-2867-6-20
[13]	Eto, I. (2010) Upstream Molecular Signaling Pathways of p27(Kip1) Expression: Effects of 4-Hydroxytamoxifen, Dexamethasone, and Retinoic Acids. Cancer Cell International, 10, 1-19. http://www.cancerci.com/content/10/1/3 http://dx.doi.org/10.1186/1475-2867-10-3
[14]	Eto, I. (2011) Upstream Molecular Signaling Pathways of p27(Kip1) Expression in Human Breast Cancer Cells in Vitro: Differential Effects of 4-Hydroxytamoxifen and Deficiency of Either D-(+)-Glucose or L-Leucine. Cancer Cell International, 11, 1-17. http://www.cancerci.com/content/11/1/31 http://dx.doi.org/10.1186/1475-2867-11-31
[15]	Kullmann, M., Goepfert, U., Siewe, B. and Hengst, L. (2002) ELAV/Hu Proteins Inhibit p27 Translation via an IRES Element in the p27 5’UTR. Genes & Development, 16, 3087-3099. http://dx.doi.org/10.1101/gad.248902
[16]	Goepfert, U., Kullmann, M. and Hengst, L. (2003) Cell Cycle-Dependent Translation of p27 Involves a Responsive Element in Its 5’-UTR That Overlaps with a uORF. Human Molecular Genetics, 12, 1767-1779. http://dx.doi.org/10.1093/hmg/ddg177
[17]	Awazu, M., Omori, S., Ishikura, K., Hida, M. and Fujita, H. (2003) The Lack of CyclinKinase Inhibitor p27Kip1 Ameliorates Progression of Diabetic Nephropathy. Journal of the American Society of Nephrology, 14, 699-708. http://dx.doi.org/10.1097/01.ASN.0000051726.41601.C0
[18]	Wolf, G. and Shankland, S.J. (2003) p27Kip1: The “Rosebud” of Diabetic Nephropathy? Journal of the American Society of Nephrology, 14, 819-922. http://dx.doi.org/10.1097/01.ASN.0000057518.58420.E4
[19]	Wolf, G., Schroeder, R., Thaiss, F., Ziyadeh, F.N., Helmchen, U. and Stahl, R.A. (1998) Glomerular Expression of p27Kip1 in Diabetic db/db Mouse: Role of Hyperglycemia. Kidney International, 53, 869-879. http://dx.doi.org/10.1111/j.1523-1755.1998.00829.x
[20]	Shankland, S.J. (1998) The Growing Role for the Cyclin Kinase Inhibitor p27Kip1 in Renal Disease. Kidney International, 54, 2241-2242. http://dx.doi.org/10.1038/4499991
[21]	Wolf, G. (2000) Cell Cycle Regulation in Diabetic Nephropathy. Kidney International, 58, S59-S66. http://dx.doi.org/10.1046/j.1523-1755.2000.07710.x
[22]	Wolf, G., Schanze, A., Stahl, R.A., Shankland, S.J. and Amann, K. (2005) p27Kip1 Knockout Mice Are Protected from Diabetic Nephropathy: Evidence for p27Kip1 Haplotype Insufficiency. Kidney International, 68, 1583-1589. http://dx.doi.org/10.1111/j.1523-1755.2005.00570.x
[23]	Wolf, G. and Ziyadeh, F.N. (2007) Cellular and Molecular Mechanisms of Proteinuria in Diabetic Nephropathy. Nephron Physiololgy, 106, 26-31. http://dx.doi.org/10.1159/000101797
[24]	Rüster, C. and Wolf, G. (2006) Renin-Angiotensin-Aldosterone System and Progression of Renal Disease. Journal of the American Society of Nephrology, 17, 2985-2991. http://dx.doi.org/10.1681/ASN.2006040356
[25]	Wolf, G. (2006) Renal Injury Due to Renin-Angiotensin-Aldosterone System Activation of the Transforming Growth Factor-β Pathway. Kidney International, 70, 1914-1919.
[26]	Loeffle, I., Hopfer, U., Koczan, D. and Wolfe, G. (2011) Type VIII Collagen Modulates TGF-β1-Induced Proliferation of Mesangial Cells. Journal of the American Society of Nephrology, 22, 649-663. http://dx.doi.org/10.1681/ASN.2010010098
[27]	Loeffler, I., Rüster, C., Franke, S., Liebisch, M. and Wolf, G. (2013) Erythropoietin Ameliorates Podocyte Injury in Advanced Diabetic Nephropathy in the db/db Mouse. American Journal of Physiology-Renal Physiology, 305, F911-F918. http://dx.doi.org/10.1152/ajprenal.00643.2012
[28]	Kanwar, Y.S., Wada, J., Sun, L., Xie, P., Wallner, E.I., Chen, S., Chugh, S. and Danesh, F.R. (2008) Diabetic Nephropathy: Mechanisms of Renal Disease Progression. Experimental Biology and Medicine (Maywood), 233, 4-11. http://dx.doi.org/10.3181/0705-MR-134
[29]	Wolf, G. (Ed.) (2006) Obesity and the Kidney. Basel, Karger.
[30]	Suzuki, S., Ohashi, N. and Kitagawa, M. (2013) Roles of the Skp2/p27 Axis in the Progression of Chronic Nephropathy. Cellular and Molecular Life Sciences, 70, 3277-3287. http://dx.doi.org/10.1007/s00018-012-1232-x
[31]	Zhong, L., Georgia, S., Tschen, S.I., Nakayama, K. and Bhushan, A. (2007) Essential Role of Skp2-Mediated p27 Degradation in Growth and Adaptive Expansion of Pancreatic β Cells. Journal of Clinical Investigation, 117, 2869-2876. http://dx.doi.org/10.1172/JCI32198
[32]	Tschen, S.I., Georgia, S., Dhawan, S. and Bhushan, A. (2011) Skp2 Is Required for Incretin Hormone-Mediated β-Cell Proliferation. Molecular Endocrinology, 25, 2134-2143. http://dx.doi.org/10.1210/me.2011-1119
[33]	Georgia, S. and Bhushan, A. (2006) p27 Regulates the Transition of β-Cells from Quiescence to Proliferation. Diabetes, 55, 2950-2956. http://dx.doi.org/10.2337/db06-0249