TY - JOUR
T1 - Par-4-dependent p53 up-regulation plays a critical role in thymoquinone-induced cellular senescence in human malignant glioma cells
AU - Subburayan, Karthikeyan
AU - Thayyullathil, Faisal
AU - Pallichankandy, Siraj
AU - Rahman, Anees
AU - Galadari, Sehamuddin
N1 - Funding Information:
This work was financially supported by grants from the Terry Fox Foundation for Cancer Research (21M093), UAE; UAE University National Research Foundation-NRF (31M097), UAE; Al Jalila Foundation (AJF201413), UAE; UAEU Program for Advanced Research (31M097), UAE; and in part from the College of Medicine and Health Sciences, UAE. The funding sources had no role in the study design, collection, analysis, data interpretation or the writing of the manuscript. We also acknowledge Core Technology Platforms at NYUAD.
Funding Information:
This work was financially supported by grants from the Terry Fox Foundation for Cancer Research ( 21M093 ), UAE; UAE University National Research Foundation-NRF ( 31M097 ), UAE; Al Jalila Foundation ( AJF201413 ), UAE; UAEU Program for Advanced Research ( 31M097 ), UAE; and in part from the College of Medicine and Health Sciences, UAE . The funding sources had no role in the study design, collection, analysis, data interpretation or the writing of the manuscript. We also acknowledge Core Technology Platforms at NYUAD.
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/7/10
Y1 - 2018/7/10
N2 - Thymoquinone (TQ), the predominant bioactive constituent present in black cumin (Nigella sativa), exerts tumor suppressive activity against a wide variety of cancer cells. Cellular senescence, characterized by stable and long term loss of proliferative capacity, acts as a potent tumor suppressive mechanism. Here, we provide evidence for the first time that TQ suppresses growth of glioma cells by potentially inducing the expression of prostate apoptosis response-4 (Par-4) tumor suppressor protein. In turn, TQ-induced Par-4 expression triggers cellular senescence, as evidenced by increasing cellular size, β-galactosidase staining, G1 phase arrest, and increased expression of senescence markers such as p53, p21, Rb, and decreased expression of lamin B1, cyclin E and cyclin depended kinase-2 (CDK-2). Further, overexpression of Par-4 significantly increases the expression of p53 and its downstream target p21, and increases β-galactosidase positive cells, while siRNA/shRNA mediated-knockdown of Par-4 reverses the TQ-induced effects. Altogether, we describe a novel mechanism of cross talk between Par-4 and p53, that plays a critical role in TQ-induced senescence in human malignant glioma cells.
AB - Thymoquinone (TQ), the predominant bioactive constituent present in black cumin (Nigella sativa), exerts tumor suppressive activity against a wide variety of cancer cells. Cellular senescence, characterized by stable and long term loss of proliferative capacity, acts as a potent tumor suppressive mechanism. Here, we provide evidence for the first time that TQ suppresses growth of glioma cells by potentially inducing the expression of prostate apoptosis response-4 (Par-4) tumor suppressor protein. In turn, TQ-induced Par-4 expression triggers cellular senescence, as evidenced by increasing cellular size, β-galactosidase staining, G1 phase arrest, and increased expression of senescence markers such as p53, p21, Rb, and decreased expression of lamin B1, cyclin E and cyclin depended kinase-2 (CDK-2). Further, overexpression of Par-4 significantly increases the expression of p53 and its downstream target p21, and increases β-galactosidase positive cells, while siRNA/shRNA mediated-knockdown of Par-4 reverses the TQ-induced effects. Altogether, we describe a novel mechanism of cross talk between Par-4 and p53, that plays a critical role in TQ-induced senescence in human malignant glioma cells.
KW - Par-4
KW - Senescence
KW - Thymoquinone
KW - p53
KW - β-galactosidase
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U2 - 10.1016/j.canlet.2018.04.009
DO - 10.1016/j.canlet.2018.04.009
M3 - Article
C2 - 29656006
AN - SCOPUS:85045753354
SN - 0304-3835
VL - 426
SP - 80
EP - 97
JO - Cancer Letters
JF - Cancer Letters
ER -