Inhibition of pancreatic cancer cell growth and induction of apoptosis with novel therapies directed against protein kinase A.

BACKGROUND Pancreatic cancer is the most lethal abdominal malignancy. Expression of the RIalpha subunit of protein kinase A (PKA) has been associated with neoplastic transformation and mitogenic signaling. The effect of PKA inhibition on pancreatic cancer cell growth and apoptosis is unknown. In pancreatic cancer cells, we sought to determine (1) whether inhibition of PKA can inhibit growth or induce apoptosis, and (2) whether growth can be inhibited by silencing of RIalpha expression. METHODS Human pancreatic cancer cells (PANC-1, MIA PaCa-2, and SUIT-2) were treated with inhibitors of PKA (H89 or PKI) and cell growth, kinase activity, and induction of apoptosis measured. Small inhibitory RNA (siRNA) directed against the RIalpha subunit was synthesized and transfected into PANC-1 cells. RESULTS H89 decreased PKA activity and inhibited pancreatic cancer cell growth. Apoptosis was also induced by H89 in PANC-1 and MIA PaCa-2 cells. PANC-1 cells express high levels of the RIalpha subunit; transfection of siRNA decreased RIalpha protein expression and inhibited growth. CONCLUSIONS Inhibition of PKA in pancreatic cancer cells induces growth arrest and apoptosis; similar effects are noted in cells with siRNA used to block RIalpha expression. Inhibition of PKA may represent a novel therapeutic strategy for the adjuvant treatment of pancreatic cancer.

[1]  S. Dhanasekaran,et al.  The polycomb group protein EZH2 is involved in progression of prostate cancer , 2002, Nature.

[2]  Douglas S. Conklin,et al.  Gene expression: RNA interference in adult mice , 2002, Nature.

[3]  B. Evers,et al.  Augmentation of sodium butyrate-induced apoptosis by phosphatidylinositol 3'-kinase inhibition in the KM20 human colon cancer cell line. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[4]  G. Tortora,et al.  Protein Kinase A as Target for Novel Integrated Strategies of Cancer Therapy , 2002, Annals of the New York Academy of Sciences.

[5]  T. Tuschl,et al.  Analysis of gene function in somatic mammalian cells using small interfering RNAs. , 2002, Methods.

[6]  A. Mercurio,et al.  Protein Kinase A Regulates Rac and Is Required for the Growth Factor-stimulated Migration of Carcinoma Cells* , 2001, The Journal of Biological Chemistry.

[7]  D. Chung,et al.  Butyrate sensitizes human colon cancer cells to TRAIL-mediated apoptosis. , 2001, Surgery.

[8]  N. Rivard,et al.  cAMP protection of pancreatic cancer cells against apoptosis induced by ERK inhibition. , 2001, Biochemical and biophysical research communications.

[9]  Sang Gyun Kim,et al.  8‐Cl‐cAMP induces cell cycle‐specific apoptosis in human cancer cells , 2001, International journal of cancer.

[10]  Y. Cho‐Chung,et al.  Compensatory Stabilization of RIIβ Protein, Cell Cycle Deregulation, and Growth Arrest in Colon and Prostate Carcinoma Cells by Antisense-directed Down-Regulation of Protein Kinase A RIα Protein , 2000 .

[11]  G. Tortora,et al.  Review Targeting of Epidermal Growth Factor Receptor and Protein Kinase A: Molecular Basis and Therapeutic Applications , 2022 .

[12]  K. Lillemoe,et al.  Pancreatic cancer: State‐of‐the‐art care , 2000, CA: a cancer journal for clinicians.

[13]  B. Evers,et al.  Downregulation of mitogen-activated protein kinases in human colon cancers. , 2000, Anticancer research.

[14]  R. Park,et al.  Cyclic adenosine monophosphate inhibits ursolic acid-induced apoptosis via activation of protein kinase A in human leukaemic HL-60 cells. , 2000, Pharmacology & toxicology.

[15]  S. Agrawal,et al.  Antitumor activity and pharmacokinetics of a mixed-backbone antisense oligonucleotide targeted to the RIalpha subunit of protein kinase A after oral administration. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[16]  P. Johnston,et al.  Increased expression of the RIα subunit of the cAMP-dependent protein kinase A is associated with advanced stage ovarian cancer , 1999, British Journal of Cancer.

[17]  R H Hruban,et al.  Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. , 1997, Annals of surgery.

[18]  Y. Cho‐Chung,et al.  cAMP-dependent protein kinase: role in normal and malignant growth. , 1995, Critical reviews in oncology/hematology.

[19]  R. Saxton,et al.  Y2 receptors decrease human pancreatic cancer growth and intracellular cyclic adenosine monophosphate levels. , 1995, Surgery.

[20]  G. Chejfec,et al.  Regulation of lewis lung carcinoma invasion and metastasis by protein kinase A , 1995, International journal of cancer.

[21]  A. Schally,et al.  Somatostatin analog RC‐160 inhibits growth of CFPAC‐1 human pancreatic cancer cells in vitro and intracellular production of cyclic adenosine monophosphate , 1995, International journal of cancer.

[22]  Y. Cho‐Chung,et al.  Protein kinase A (PK-A) regulatory subunit expression in colorectal cancer and related mucosa. , 1994, British Journal of Cancer.

[23]  Alicia Samuels,et al.  Cancer Statistics, 2003 , 2003, CA: a cancer journal for clinicians.

[24]  R. Bold,et al.  Experimental gene therapy of human colon cancer. , 1994, Surgery.

[25]  E. Krebs,et al.  Protein Kinases* *Support of the National Institutes of Arthritis and Metabolic Diseases, NIH, U. S. Public Health Service (AM 12842), the Muscular Dystrophy Association of America, and the American Heart Association is acknowledged. , 1972 .