Src activation by β-adrenoreceptors is a key switch for tumour metastasis.
Noradrenaline can modulate multiple cellular functions important for cancer progression; however, how this single extracellular signal regulates such a broad array of cellular processes is unknown. Here we identify Src as a key regulator of phosphoproteomic signalling networks activated in response to beta-adrenergic signalling in cancer cells. These results also identify a new mechanism of Src phosphorylation that mediates beta-adrenergic/PKA regulation of downstream networks, thereby enhancing tumour cell migration, invasion and growth. In human ovarian cancer samples, high tumoural noradrenaline levels were correlated with high pSrc(Y419) levels. Moreover, among cancer patients, the use of beta blockers was significantly associated with reduced cancer-related mortality. Collectively, these data provide a pivotal molecular target for disrupting neural signalling in the tumour microenvironment.
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Guillermo N
GN
Armaiz-Pena
Julie K
JK
Allen
Anthony
A
Cruz
Rebecca L
RL
Stone
Alpa M
AM
Nick
Yvonne G
YG
Lin
Liz Y
LY
Han
Lingegowda S
LS
Mangala
Gabriel J
GJ
Villares
Pablo
P
Vivas-Mejia
Cristian
C
Rodriguez-Aguayo
Archana S
AS
Nagaraja
Kshipra M
KM
Gharpure
Zheng
Z
Wu
Robert D
RD
English
Kizhake V
KV
Soman
Mian M K
MM
Shahzad
Mian M K
MM
Shazhad
Maya
M
Zigler
Michael T
MT
Deavers
Alexander
A
Zien
Theodoros G
TG
Soldatos
David B
DB
Jackson
John E
JE
Wiktorowicz
Madeline
M
Torres-Lugo
Tom
T
Young
Koen
K
De Geest
Gary E
GE
Gallick
Menashe
M
Bar-Eli
Gabriel
G
Lopez-Berestein
Steve W
SW
Cole
Gustavo E
GE
Lopez
Susan K
SK
Lutgendorf
Anil K
AK
Sood
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009638:Norepinephrine / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D016019:Survival Analysis; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000737:chemistry / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D010768:Phosphoserine; D014443:Tyrosine; D000242:Cyclic AMP; D019061:src-Family Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D009638:Norepinephrine