Untitled - Red Temática de investigación cooperativa en cáncer

O-10
INFLUENCE OF LKB1/STK11 IN GENE EXPRESSION PATTERNS INDUCED BY ENER-
GY STRESS IN LUNG CANCER CELL LINES
GONÇALVES RESTANI R 1 , RODRÍGUEZ NIETO S 1 , SÁNCHEZ CESPEDES M 1
1
PROGRAMA EPIGENETICA I BIOLOGIA DEL CANCER-PEBC/BELLVITGE BIOMEDICAL RESEARCH INSTI
TUTE-IDIBELL BARCELONA (RD06/0020/0062)
The LKB1 gene, also known as STK11 is frequently mutated or deleted in several types of
cancer. Recently, it has been shown that one third of adenocarcinomas carry LKB1 somatic
mutations.
One of the key downstream kinases of LKB1 is the AMP-activated protein kinase (AMPK),
a serine/threonine kinase that serves as a master regulator of energy metabolism. In this
work, we show that upon induced energy stress either by glucose depletion or using AICAR
(5-aminoimidazole-4-carboxamide-1-β-d-riboruranoside), the presence of functional LKB1
is required to regulate the expression of different genes, including the zinc finger transcriptional
activator KLF15 which is involved in regulating gene expression during growth,
differentiation, adipogenesis and gluconeogenesis.
We observed that only those lung cancer cell lines expressing wild type LKB1 are able regulate
the expression of KLF15 under energetic stress, while mutant cell lines do not have
this capability.
Further, we performed either down-regulation or ectopic expression of LKB1 in wild type or
mutant cell lines, respectively, and confirmed these observations.
In addition, upon energy stress conditions, only in LKB1 wild-type cell lines were able to
restore the LKB1/AMPK pathway as evidenced by the phosphorylation of acetyl-CoA carboxylase
(ACC), a target of AMPK. These observations were confirmed after ectopically
restituting LKB1 in mutant cell lines.
Finally, ectopic expression of a dominant negative form of AMPK’s catalytic subunit (alpha-
K95R) prevented the up-regulation KLF15, demonstrating that the pathway requires a
functional AMPK to control the levels of expression of KLF15. Altogether, these results show
the relationship between LKB1, energy metabolism and KLF15.
O-11
IDENTIFICATION OF DIFFERENTIAL GENOMIC AND PROTEOMIC PROFILES ASSO-
CIATED WITH BONE METASTASES IN PROSTATE CANCER
GARCÍA M 1 , RIGAU M 1 , GOMIS R 2 , MOROTE J 3 , REVENTÓS J 1 , DOLL A 1
1
RESEARCH INSTITUTE VALL HEBRON UNIVERSITY BARCELONA (RD06/0020/0058)
2
INSTITUTE FOR RESEARCH IN BIOMEDICINE, BARCELONA
3
VALL HEBRON HOSPITAL, BARCELONA (RD06/0020/0058)
Bone metastases are a frequent and devastating complication in cancer patients, occurring
predominantly in patients with prostate or breast cancer, but also in lung, thyroid, kidney,
and stomach cancer patients. Prostate cancer (PCa) is the most common diagnosed cancer
in men in western world, and skeletal metastases occur in as many as 90% of patients with
advanced PCa. Bone metastatic disease, usually incurable, also has serious clinical manifestations
like severe pain, pathologic fractures, hypercalcemia and spinal cord compression,
making this devastating cancer complication an important and costly health issue.
Objective: To identify novel molecules responsible for the bone metastatic PCa process at
the miRNA, gene and protein level.
Methodology: We serially performed intracardiacal injections (i.c.) of human PCa (PC-3)
stably luciferase expressing cells in male nude mice in order to select a highly bone metastatic
PCa cell population. Cells from bone metastasis were isolated, expanded in culture
and re-injected again into another group of mice. We repeated this step three times. We
used the IVIS System to monitor tumor growth and detect metastases in the living animal.
Genomic and proteomic approaches were done comparing the highly bone metastatic PCa
cell population to the parental one.
Results: The highly bone metastatic PCa cell population obtained by in vivo selection
showed an increased bone metastasis pattern when they were injected in vivo.
Differential genomic profiles of specific miRNAs, genes and proteins with a FC>2 and p-
value