Abstract
Elevated oxidative stress is an aberration seen in many solid tumors, and exploiting this biochemical difference has the potential to enhance the efficacy of anticancer agents. Homeostasis of reactive oxygen species (ROS) is important for normal cell function, but excessive production of ROS can result in cellular toxicity, and therefore ROS levels must be balanced finely. Here, we highlight the relationship between the extracellular matrix and ROS production by reporting a novel function of the matricellular protein Fibulin-5 (Fbln5). We used genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDAC) and found that mutation of the integrin-binding domain of Fbln5 led to decreased tumor growth, increased survival, and enhanced chemoresponse to standard PDAC therapies. Through mechanistic investigations, we found that improved survival was due to increased levels of oxidative stress in Fbln5-mutant tumors. Furthermore, loss of the Fbln5-integrin interaction augmented fibronectin signaling, driving integrin-induced ROS production in a 5-lipooxygenase-dependent manner. These data indicate that Fbln5 promotes PDAC progression by functioning as a molecular rheostat that modulates cell-ECM interactions to reduce ROS production, and thus tip the balance in favor of tumor cell survival and treatment-refractory disease.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5058-5069 |
| Number of pages | 12 |
| Journal | Cancer Research |
| Volume | 75 |
| Issue number | 23 |
| DOIs | |
| State | Published - Dec 1 2015 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Fibulin-5 blocks microenvironmental ROS in pancreatic cancer. / Wang, Miao; Topalovski, Mary; Toombs, Jason E.; Wright, Christopher M.; Moore, Zachary R.; Boothman, David A.; Yanagisawa, Hiromi; Wang, Huamin; Witkiewicz, Agnieszka; Castrillon, Diego H.; Brekken, Rolf A.
In: Cancer Research, Vol. 75, No. 23, 01.12.2015, p. 5058-5069.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Fibulin-5 blocks microenvironmental ROS in pancreatic cancer
AU - Wang, Miao
AU - Topalovski, Mary
AU - Toombs, Jason E.
AU - Wright, Christopher M.
AU - Moore, Zachary R.
AU - Boothman, David A.
AU - Yanagisawa, Hiromi
AU - Wang, Huamin
AU - Witkiewicz, Agnieszka
AU - Castrillon, Diego H.
AU - Brekken, Rolf A.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - Elevated oxidative stress is an aberration seen in many solid tumors, and exploiting this biochemical difference has the potential to enhance the efficacy of anticancer agents. Homeostasis of reactive oxygen species (ROS) is important for normal cell function, but excessive production of ROS can result in cellular toxicity, and therefore ROS levels must be balanced finely. Here, we highlight the relationship between the extracellular matrix and ROS production by reporting a novel function of the matricellular protein Fibulin-5 (Fbln5). We used genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDAC) and found that mutation of the integrin-binding domain of Fbln5 led to decreased tumor growth, increased survival, and enhanced chemoresponse to standard PDAC therapies. Through mechanistic investigations, we found that improved survival was due to increased levels of oxidative stress in Fbln5-mutant tumors. Furthermore, loss of the Fbln5-integrin interaction augmented fibronectin signaling, driving integrin-induced ROS production in a 5-lipooxygenase-dependent manner. These data indicate that Fbln5 promotes PDAC progression by functioning as a molecular rheostat that modulates cell-ECM interactions to reduce ROS production, and thus tip the balance in favor of tumor cell survival and treatment-refractory disease.
AB - Elevated oxidative stress is an aberration seen in many solid tumors, and exploiting this biochemical difference has the potential to enhance the efficacy of anticancer agents. Homeostasis of reactive oxygen species (ROS) is important for normal cell function, but excessive production of ROS can result in cellular toxicity, and therefore ROS levels must be balanced finely. Here, we highlight the relationship between the extracellular matrix and ROS production by reporting a novel function of the matricellular protein Fibulin-5 (Fbln5). We used genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDAC) and found that mutation of the integrin-binding domain of Fbln5 led to decreased tumor growth, increased survival, and enhanced chemoresponse to standard PDAC therapies. Through mechanistic investigations, we found that improved survival was due to increased levels of oxidative stress in Fbln5-mutant tumors. Furthermore, loss of the Fbln5-integrin interaction augmented fibronectin signaling, driving integrin-induced ROS production in a 5-lipooxygenase-dependent manner. These data indicate that Fbln5 promotes PDAC progression by functioning as a molecular rheostat that modulates cell-ECM interactions to reduce ROS production, and thus tip the balance in favor of tumor cell survival and treatment-refractory disease.
UR - http://www.scopus.com/inward/record.url?scp=84955476499&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84955476499&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-15-0744
DO - 10.1158/0008-5472.CAN-15-0744
M3 - Article
C2 - 26577699
AN - SCOPUS:84955476499
VL - 75
SP - 5058
EP - 5069
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 23
ER -