TY - JOUR
T1 - ΔNp63α confers tumor cell resistance to cisplatin through the AKT1 transcriptional regulation
AU - Sen, Tanusree
AU - Sen, Nilkantha
AU - Brait, Mariana
AU - Begum, Shahnaz
AU - Chatterjee, Aditi
AU - Hoque, Mohammad Obaidul
AU - Ratovitski, Edward
AU - Sidransky, David
PY - 2011/2/1
Y1 - 2011/2/1
N2 - Strategies to address resistance to platin drugs are greatly needed in human epithelial cancers (e.g., ovarian, head/neck, and lung) where platins are used widely and resistance occurs commonly. We found that upon ΔNp63α overexpression, AKT1 and phospho-AKT1 levels are upregulated in cancer cells. Investigations using gel-shift, chromatin immunoprecipitation and functional reporter assays implicated ΔNp63α in positive regulation of AKT1 transcription. Importantly, we found that ΔNp63α, AKT1, and phospho-AKT levels are greater in 2008CI3 CDDP-resistant ovarian cancer cells than in 2008 CDDP-sensitive cells. siRNA-mediated knockdown of ΔNp63α expression dramatically decreased AKT1 expression, whereas knockdown of either ΔNp63α or AKT1 decreased cell proliferation and increased death of ovarian and head/neck cancer cells. Conversely, enforced expression of ΔNp63α increased cancer cell proliferation and reduced apoptosis. Together, our findings define a novel ΔNp63α-dependent regulatory mechanism for AKT1 expression and its role in chemotherapeutic resistance of ovarian and head/neck cancer cells.
AB - Strategies to address resistance to platin drugs are greatly needed in human epithelial cancers (e.g., ovarian, head/neck, and lung) where platins are used widely and resistance occurs commonly. We found that upon ΔNp63α overexpression, AKT1 and phospho-AKT1 levels are upregulated in cancer cells. Investigations using gel-shift, chromatin immunoprecipitation and functional reporter assays implicated ΔNp63α in positive regulation of AKT1 transcription. Importantly, we found that ΔNp63α, AKT1, and phospho-AKT levels are greater in 2008CI3 CDDP-resistant ovarian cancer cells than in 2008 CDDP-sensitive cells. siRNA-mediated knockdown of ΔNp63α expression dramatically decreased AKT1 expression, whereas knockdown of either ΔNp63α or AKT1 decreased cell proliferation and increased death of ovarian and head/neck cancer cells. Conversely, enforced expression of ΔNp63α increased cancer cell proliferation and reduced apoptosis. Together, our findings define a novel ΔNp63α-dependent regulatory mechanism for AKT1 expression and its role in chemotherapeutic resistance of ovarian and head/neck cancer cells.
UR - http://www.scopus.com/inward/record.url?scp=79551524391&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79551524391&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-10-1481
DO - 10.1158/0008-5472.CAN-10-1481
M3 - Article
C2 - 21266360
AN - SCOPUS:79551524391
SN - 0008-5472
VL - 71
SP - 1167
EP - 1176
JO - Cancer Research
JF - Cancer Research
IS - 3
ER -