Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Targeted Oncology
Published in: Targeted Oncology 2/2016

01-04-2016 | Original Research Article

Inhibition of Survival Pathways MAPK and NF-kB Triggers Apoptosis in Pancreatic Ductal Adenocarcinoma Cells via Suppression of Autophagy

Authors: Daniela Laura Papademetrio, Silvina Laura Lompardía, Tania Simunovich, Susana Costantino, Cintia Yamila Mihalez, Victoria Cavaliere, Élida Álvarez

Published in: Targeted Oncology | Issue 2/2016

Login to get access

Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a survival rate of 4–6 months from diagnosis. PDAC is the fourth leading cause of cancer-related death in the Western world, with a mortality rate of 10 cases per 100,000 population. Chemotherapy constitutes only a palliative strategy, with limited effects on life expectancy.

Aims

To investigate the biological response of PDAC to mitogen-activated protein kinase (MAPK) and NF-kappaB (NF-kB) inhibitors and the role of autophagy in the modulation of these signaling pathways in order to address the challenge of developing improved medical protocols for patients with PDAC.

Methods

Two ATCC cell lines, MIAPaCa-2 and PANC-1, were used as PDAC models. Cells were exposed to inhibitors of MAPK or NF-kB survival pathways alone or after autophagy inhibition. Several aspects were analyzed, as follows: cell proliferation, by [3H]TdR incorporation; cell death, by TUNEL assay, regulation of autophagy by LC3-II expression level and modulation of pro-and anti-apoptotic proteins by Western blot.

Results

We demonstrated that the inhibition of the MAPK and NF-kB survival pathways with U0126 and caffeic acid phenethyl ester (CAPE), respectively, produced strong inhibition of pancreatic tumor cell growth without inducing apoptotic death. Interestingly, U0126 and CAPE induced apoptosis after autophagy inhibition in a caspase-dependent manner in MIA PaCa-2 cells and in a caspase-independent manner in PANC-1 cells.

Conclusions

Here we present evidence that allows us to consider a combined therapy regimen comprising an autophagy inhibitor and a MAPK or NF-kB pathway inhibitor as a possible treatment strategy for pancreatic cancer.
https://static-content.springer.com/image/art%3A10.1007%2Fs11523-015-0388-3/MediaObjects/11523_2015_388_Figa_HTML.gif
Literature
1.
2.
Hidalgo M (2012) New insights into pancreatic cancer biology. Ann Oncol 23(Suppl 10):135–8CrossRef
3.
4.
5.
Garcia MG, Alaniz LD, Cordo Russo RI et al (2009) PI3K/Akt inhibition modulates multidrug resistance and activates NFkB in murine Lymphoma cell lines. Leuk Res 33:288–96CrossRefPubMed
6.
Cox AD, Der CJ (1997) Farnesyltransferase inhibitors and cancer treatment: targeting simply Ras? Biochim Biophys Acta 1333(1):F51–71PubMed
7.
Muerkoster S, Arlt A, Sipos B et al (2005) Increased expression of the E3-ubiquitin ligase receptor subunit betaTRCP1 relates to constitutive nuclear factor-kappaB activation and chemoresistance in pancreatic carcinoma cells. Cancer Res 65(4):1316–24CrossRefPubMed
8.
Aksamitiene E, Kiyatkin A, Kholodenko BN (2012) Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance. Biochem Soc Trans 40:139–46CrossRefPubMed
9.
De Luca A, Maiello MR, D'Alessio A et al (2012) The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets 16:S17–27CrossRefPubMed
10.
Shimizu T, Tolcher AW, Papadopoulos KP et al (2012) The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clin Cancer Res 18:2316–25CrossRefPubMed
11.
Wang LH (2014) LiY, Yang SN, et al. Gambogic acid synergistically potentiates cisplatin-induced apoptosis in non-small-cell lung cancer through suppressing NF-κB and MAPK/HO-1 signalling. Br J Cancer 110(2):34–52CrossRef
12.
Sylvester RJ, van der Meijden AP, Oosterlinck W et al (2006) Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 49:466–75CrossRefPubMed
13.
Vaux DL, Silke J (2003) Mammalian mitochondrial IAP binding proteins. Biochem Biophys Res Commun 304:499–504CrossRefPubMed
14.
Wei Y, Fan T, Yu M (2008) Inhibitor of apoptosis proteins and apoptosis. Acta Biochim Biophys Sin (Shanghai) 40:278–88CrossRef
15.
16.
Dubrez-Daloz L, Dupoux A, Cartier J (2008) IAPs: more than just inhibitors of apoptosis proteins. Cell Cycle 7:1036–46CrossRefPubMed
17.
LaCasse EC, Mahoney DJ, Cheung HH et al (2008) IAP-targeted therapies for cancer. Oncogene 27:6252–75CrossRefPubMed
18.
Vucic D, Fairbrother WJ (2007) The inhibitor of apoptosis proteins as therapeutic targets in cancer. Clin Cancer Res 13:5995–6000CrossRefPubMed
19.
20.
21.
Kirkegaard K, Taylor MP, Jackson WT (2004) Cellular autophagy: surrender, avoidance and subversion by microorganisms. Nat Rev Microbiol 2(4):301–14CrossRefPubMed
22.
Ogawa M, Yoshimori T, Suzuki T et al (2005) Escape of intracellular Shigella from autophagy. Science 307(5710):727–31CrossRefPubMed
23.
Hara T, Nakamura K, Matsui M et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441(7095):885–9CrossRefPubMed
24.
Komatsu M, Waguri S, Chiba T et al (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441(7095):880–4CrossRefPubMed
25.
Liang XH, Jackson S, Seaman M et al (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402(6762):672–6CrossRefPubMed
26.
Liang XH, Yu J, Brown K et al (2001) Beclin 1 contains a leucine-rich nuclear export signal that is required for its autophagy and tumor suppressor function. Cancer Res 61(8):3443–9PubMed
27.
Ravikumar B, Berger Z, Vacher C et al (2006) Rapamycin pre-treatment protects against apoptosis. Hum Mol Genet 15(7):1209–16CrossRefPubMed
28.
Papademetrio DL, Cavaliere V, Simunovich T et al (2014) Interplay between autophagy and apoptosis in pancreatic tumors in response to gemcitabine. Target Oncol 9(2):123–34CrossRefPubMed
29.
Kabeya Y, Mizushima N, Ueno T et al (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19(21):5720–8CrossRefPubMedPubMedCentral
30.
Rubinsztein DC, Cuervo AM, Ravikumar B et al (2009) In search of an "autophagomometer". Autophagy 5(5):585–9CrossRefPubMed
31.
Conroy T, Desseigne F, Ychou M et al (2001) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:1817–25CrossRef
32.
Hill R, Rabb M, Madureira PA et al (2013) Gemcitabine-mediated tumour regression and p53-dependent gene expression: implications for colon and pancreatic cancer therapy. Cell Death Dis 4:e791CrossRefPubMedPubMedCentral
33.
Jones S, Zhang X, Parsons DW et al (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–6CrossRefPubMedPubMedCentral
34.
35.
36.
Chen Z, Cheng K, Walton Z et al (2012) A murine lung cancer coclinical trial identifies genetic modifiers of therapeutic response. Nature 483(7391):613–7CrossRefPubMedPubMedCentral
37.
Jänne PA, Shaw AT, Pereira JR et al (2013) Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 14:38–47CrossRefPubMed
38.
McCubrey JA, Steelman LS, Chappell WH et al (2012) Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance. Oncotarget 3:1068–111CrossRefPubMedPubMedCentral
39.
Fujioka S, Sclabas GM, Schmidt C et al (2003) Function of nuclear factor kappaB in pancreatic cancer metastasis. Clin Cancer Res 9:346–54PubMed
40.
Hu L, Shi Y, Hsu JH et al (2003) Downstream effectors of oncogenic ras in multiple myeloma cells. Blood 101:3126–35CrossRefPubMed
41.
Mayo MW, Wang CY, Cogswell PC et al (1997) Requirement of NF-kappaB activation to suppress p53-independent apoptosis induced by oncogenic Ras. Science 278:1812–5CrossRefPubMed
42.
Li L, Aggarwal BB, Shishodia S et al (2004) Nuclear factor-kappaB and IkappaB kinase are constitutively active in human pancreatic cells, and their down-regulation by curcumin (diferuloylmethane) is associated with the suppression of proliferation and the induction of apoptosis. Cancer 101:2351–62CrossRefPubMed
43.
44.
Yamamoto Y, Gaynor RB (2001) Role of the NF-kappaB pathway in the pathogenesis of human disease states. Curr Mol Med 1:287–96CrossRefPubMed
45.
Aggarwal BB, Takada Y, Shishodia S et al (2004) Nuclear transcription factor NF-kappa B: role in biology and medicine. Indian J Exp Biol 42:341–53PubMed
46.
Karin M, Cao Y, Greten FR et al (2002) NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2:301–10CrossRefPubMed
47.
Garg A, Aggarwal BB (2002) Nuclear transcription factor-kappaB as a target for cancer drug development. Leukemia 16:1053–68CrossRefPubMed
48.
49.
Cai X, Lu W, Yang Y et al (2013) Digitoflavone inhibits IκBα kinase and enhances apoptosis induced by TNFα through downregulation of expression of nuclear factor κB-regulated gene products in human pancreatic cancer cells. PLoS One 8(10):e77126CrossRefPubMedPubMedCentral
50.
Cavaliere V, Papademetrio DL, Lorenzetti M et al (2009) Caffeic Acid Phenylethyl Ester and MG-132 have apoptotic and antiproliferative effects on Leukemic cells but not on normal mononuclear cells. Transl Oncol 2(1):46–58CrossRefPubMedPubMedCentral
51.
Velculescu VE (1999) Essay: Amersham Pharmacia Biotech & Science prize. Tantalizing transcriptomes SAGE and its use in global gene expression analysis. Science 286(5444):1491–2CrossRefPubMed
52.
Altieri DC (2008) Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 8(1):61–70CrossRefPubMed
53.
Sarela AI, Macadam RC, Farmery SM et al (2000) Expression of the antiapoptosis gene, survivin, predicts death from recurrent colorectal carcinoma. Gut 46(5):645–50CrossRefPubMedPubMedCentral
54.
Monzo M, Rosell R, Felip E et al (1999) A novel anti-apoptosis gene: Re-expression of survivin messenger RNA as a prognosis marker in non-small-cell lung cancers. J Clin Oncol 17(7):2100–4PubMed
55.
Shariat SF, Lotan Y, Saboorian H et al (2004) Survivin expression is associated with features of biologically aggressive prostate carcinoma. Cancer 100(4):751–7CrossRefPubMed
56.
Tanaka K, Iwamoto S, Gon G et al (2000) Expression of survivin and its relationship to loss of apoptosis in breast carcinomas. Clin Can 6(1):127–34
57.
Jourdan M, Reme T, Goldschmidt H et al (2009) Gene expression of anti- and pro-apoptotic proteins in malignant and normal plasma cells. Br J Haematol 145(1):45–58CrossRefPubMedPubMedCentral
58.
Cheng SM, Chang YC, Liu CY et al (2015) YM155 down-regulates survivin and XIAP, modulates autophagy and induces autophagy-dependent DNA damage in breast cancer cells. Br J Pharmacol 172(1):214–34CrossRefPubMed
59.
Wang J, Whiteman MW, Lian H et al (2009) A Non-canonical MEK/ERK Signaling Pathway Regulates Autophagy via Regulating Beclin 1. J Biol Chem 284(32):21412–24CrossRefPubMedPubMedCentral
60.
Pattingre S, Bauvy C, Codogno PZ (2003) Amino acids interfere with the ERK1⁄ 2-dependent control of macroautophagy by controlling the activation of Raf-1 in human colon cancer HT-29 cells. J Biol Chem 278:16667–74CrossRefPubMed
61.
Ellington AA, Berhow MA, Singletary KW (2006) Inhibition of Akt signaling and enhanced ERK1⁄ 2 activity are involved in induction of macroautophagy by triterpenoid B-group soyasaponins in colon cancer cells. Carcinogenesis 27:298–306CrossRefPubMed
62.
Copetti T, Demarchi F, Schneider C (2009) p65/RelA binds and activates the beclin 1 promoter. Autophagy 5(6):858–9CrossRefPubMed
63.
Vadlamudi RK, Shin J (1998) Genomic structure and promoter analysis of the p62 gene encoding a nonproteasomal multiubiquitin chain binding protein. FEBS Lett 435:138–42CrossRefPubMed
64.
David A (2014) An autophagic switch in the response of tumor cells to radiation and chemotherapy. Biochem Pharmacol 90:208–11CrossRef
65.
Metadata
Title
Inhibition of Survival Pathways MAPK and NF-kB Triggers Apoptosis in Pancreatic Ductal Adenocarcinoma Cells via Suppression of Autophagy
Authors
Daniela Laura Papademetrio
Silvina Laura Lompardía
Tania Simunovich
Susana Costantino
Cintia Yamila Mihalez
Victoria Cavaliere
Élida Álvarez
Publication date
01-04-2016
Publisher
Springer International Publishing
Published in
Targeted Oncology / Issue 2/2016
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI
https://doi.org/10.1007/s11523-015-0388-3

Other articles of this Issue 2/2016

Targeted Oncology 2/2016 Go to the issue

Original Research Article

RETRACTED ARTICLE: MicroRNA-216b is Down-Regulated in Human Gastric Adenocarcinoma and Inhibits Proliferation and Cell Cycle Progression by Targeting Oncogene HDAC8

Review Article

Expert Recommendations for First-Line Management of Metastatic Renal Cell Carcinoma in Special Subpopulations

Adis Drug Evaluation

Carfilzomib Triple Combination Therapy: A Review in Relapsed Multiple Myeloma

Short Communication

Effect of Renal Impairment on the Pharmacokinetics and Safety of Axitinib

Adis Drug Evaluation

Dinutuximab: A Review in High-Risk Neuroblastoma

Original Research

Impact of Continuing First-Line EGFR Tyrosine Kinase Inhibitor Therapy Beyond RECIST Disease Progression in Patients with Advanced EGFR-Mutated Non-Small-Cell Lung Cancer (NSCLC): Retrospective GFPC 04-13 Study
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits