RacGAP1 is a novel downstream effector of E2F7-dependent resistance to doxorubicin and is prognostic for overall survival in squamous cell carcinoma

Hazar-Rethinam, Mehlika, de Long, Lilia Merida, Gannon, Orla M., Boros, Samuel, Vargas, Ana Cristina, Dzienis, Marcin, Mukhopadhyay, Pamela, Saenz-Ponce, Natalia, Dantzic, Daniel D. E., Simpson, Fiona and Saunders, Nicholas A. (2015) RacGAP1 is a novel downstream effector of E2F7-dependent resistance to doxorubicin and is prognostic for overall survival in squamous cell carcinoma. Molecular Cancer Therapeutics, 14 8: 1939-1950. doi:10.1158/1535-7163.MCT-15-0076


Author Hazar-Rethinam, Mehlika
de Long, Lilia Merida
Gannon, Orla M.
Boros, Samuel
Vargas, Ana Cristina
Dzienis, Marcin
Mukhopadhyay, Pamela
Saenz-Ponce, Natalia
Dantzic, Daniel D. E.
Simpson, Fiona
Saunders, Nicholas A.
Title RacGAP1 is a novel downstream effector of E2F7-dependent resistance to doxorubicin and is prognostic for overall survival in squamous cell carcinoma
Journal name Molecular Cancer Therapeutics   Check publisher's open access policy
ISSN 1535-7163
1538-8514
Publication date 2015-08-01
Year available 2015
Sub-type Article (original research)
DOI 10.1158/1535-7163.MCT-15-0076
Open Access Status Not Open Access
Volume 14
Issue 8
Start page 1939
End page 1950
Total pages 12
Place of publication Philadelphia, PA, United States
Publisher American Association for Cancer Research
Language eng
Abstract We have previously shown that E2F7 contributes to drug resistance in head and neck squamous cell carcinoma (HNSCC) cells. Considering that dysregulation of responses to chemotherapy-induced cytotoxicity is one of the major reasons for treatment failure in HNSCC, identifying the downstream effectors that regulate E2F7-dependent sensitivity to chemotherapeutic agents may have direct clinical impact. We used transcriptomic profiling to identify candidate pathways that contribute to E2F7-dependent resistance to doxorubicin. We then manipulated the expression of the candidate pathway using overexpression and knockdown in in vitro and in vivo models of SCC to demonstrate causality. In addition, we examined the expression of E2F7 and RacGAP1 in a custom tissue microarray (TMA) generated from HNSCC patient samples. Transcriptomic profiling identified RacGAP1 as a potential mediator of E2F7-dependent drug resistance. We validated E2F7-dependent upregulation of RacGAP1 in doxorubicin-insensitive SCC25 cells. Extending this, we found that selective upregulation of RacGAP1 induced doxorubicin resistance in previously sensitive KJDSV40. Similarly, stable knockdown of RacGAP1 in insensitive SCC25 cells induced sensitivity to doxorubicin in vitro and in vivo. RacGAP1 expression was validated in a TMA, and we showed that HNSCCs that over-express RacGAP1 are associated with a poorer patient overall survival. Furthermore, E2F7-induced doxorubicin resistance was mediated via RacGAP1-dependent activation of AKT. Finally, we show that SCC cells deficient in RacGAP1 grow slower and are sensitized to the cytotoxic actions of doxorubicin in vivo. These findings identify RacGAP1 overexpression as a novel prognostic marker of survival and a potential target to sensitize SCC to doxorubicin.
Formatted abstract
We have previously shown that E2F7 contributes to drug resistance in head and neck squamous cell carcinoma (HNSCC) cells. Considering that dysregulation of responses to chemotherapy-induced cytotoxicity is one of the major reasons for treatment failure in HNSCC, identifying the downstream effectors that regulate E2F7-dependent sensitivity to chemotherapeutic agents may have direct clinical impact. We used transcriptomic profiling to identify candidate pathways that contribute to E2F7-dependent resistance to doxorubicin. We then manipulated the expression of the candidate pathway using overexpression and knockdown in in vitro and in vivo models of SCC to demonstrate causality. In addition, we examined the expression of E2F7 and RacGAP1 in a custom tissue microarray (TMA) generated from HNSCC patient samples. Transcriptomic profiling identified RacGAP1 as a potential mediator of E2F7-dependent drug resistance. We validated E2F7-dependent upregulation of RacGAP1 in doxorubicin-insensitive SCC25 cells. Extending this, we found that selective upregulation of RacGAP1 induced doxorubicin resistance in previously sensitive KJDSV40. Similarly, stable knockdown of RacGAP1 in insensitive SCC25 cells induced sensitivity to doxorubicin in vitro and in vivo. RacGAP1 expression was validated in a TMA, and we showed that HNSCCs that overexpress RacGAP1 are associated with a poorer patient overall survival. Furthermore, E2F7-induced doxorubicin resistance was mediated via RacGAP1-dependent activation of AKT. Finally, we show that SCC cells deficient in RacGAP1 grow slower and are sensitized to the cytotoxic actions of doxorubicin in vivo. These findings identify RacGAP1 overexpression as a novel prognostic marker of survival and a potential target to sensitize SCC to doxorubicin.
Keyword Cancer progression
Breast cancer
Expression
Head
Neck
Rac
Differentiation
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID APP1049182
APP1025479
WRI2011-17
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
UQ Diamantina Institute Publications
 
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