Autophagy Regulated by Gain of Function Mutant p53 Enhances Proteasomal Inhibitor-Mediated Cell Death through Induction of ROS and ERK in Lung Cancer Cells
المؤلفون المشاركون
Saini, Heena
Hakeem, Ifrah
Mukherjee, Sudeshna
Chowdhury, Shibasish
Chowdhury, Rajdeep
المصدر
العدد
المجلد 2019، العدد 2019 (31 ديسمبر/كانون الأول 2019)، ص ص. 1-17، 17ص.
الناشر
Hindawi Publishing Corporation
تاريخ النشر
2019-01-06
دولة النشر
مصر
عدد الصفحات
17
التخصصات الرئيسية
الملخص EN
Mutations in p53, especially gain of function (GOF) mutations, are highly frequent in lung cancers and are known to facilitate tumor aggressiveness.
Yet, the links between mutant GOF-p53 and lung cancers are not well established.
In the present study, we set to examine how we can better sensitize resistant GOF-p53 lung cancer cells through modulation of cellular protein degradation machineries, proteasome and autophagy.
H1299 p53 null lung cancer cells were stably transfected with R273H mutant GOF-p53 or wild-type (wt) p53 or empty vectors.
The presence of R273H-P53 conferred the cancer cells with drug resistance not only against the widely used chemotherapeutic agents like cisplatin (CDDP) or 5-flurouracil (5-FU) but also against potent alternative modes of therapy like proteasomal inhibition.
Therefore, there is an urgent need for new strategies that can overcome GOF-p53 induced drug resistance and prolong patient survival following failure of standard therapies.
We observed that the proteasomal inhibitor, peptide aldehyde N-acetyl-leu-leu-norleucinal (commonly termed as ALLN), caused an activation of cellular homeostatic machinery, autophagy in R273H-P53 cells.
Interestingly, inhibition of autophagy by chloroquine (CQ) alone or in combination with ALLN failed to induce enhanced cell death in the R273H-P53 cells; however, in contrast, an activation of autophagy by serum starvation or rapamycin increased sensitivity of cells to ALLN-induced cytotoxicity.
An activated autophagy was associated with increased ROS and ERK signaling and an inhibition of either ROS or ERK signaling resulted in reduced cytotoxicity.
Furthermore, inhibition of GOF-p53 was found to enhance autophagy resulting in increased cell death.
Our findings provide novel insights pertaining to mechanisms by which a GOF-p53 harboring lung cancer cell is better sensitized, which can lead to the development of advanced therapy against resistant lung cancer cells.
نمط استشهاد جمعية علماء النفس الأمريكية (APA)
Saini, Heena& Hakeem, Ifrah& Mukherjee, Sudeshna& Chowdhury, Shibasish& Chowdhury, Rajdeep. 2019. Autophagy Regulated by Gain of Function Mutant p53 Enhances Proteasomal Inhibitor-Mediated Cell Death through Induction of ROS and ERK in Lung Cancer Cells. Journal of Oncology،Vol. 2019, no. 2019, pp.1-17.
https://search.emarefa.net/detail/BIM-1184397
نمط استشهاد الجمعية الأمريكية للغات الحديثة (MLA)
Saini, Heena…[et al.]. Autophagy Regulated by Gain of Function Mutant p53 Enhances Proteasomal Inhibitor-Mediated Cell Death through Induction of ROS and ERK in Lung Cancer Cells. Journal of Oncology No. 2019 (2019), pp.1-17.
https://search.emarefa.net/detail/BIM-1184397
نمط استشهاد الجمعية الطبية الأمريكية (AMA)
Saini, Heena& Hakeem, Ifrah& Mukherjee, Sudeshna& Chowdhury, Shibasish& Chowdhury, Rajdeep. Autophagy Regulated by Gain of Function Mutant p53 Enhances Proteasomal Inhibitor-Mediated Cell Death through Induction of ROS and ERK in Lung Cancer Cells. Journal of Oncology. 2019. Vol. 2019, no. 2019, pp.1-17.
https://search.emarefa.net/detail/BIM-1184397
نوع البيانات
مقالات
لغة النص
الإنجليزية
الملاحظات
Includes bibliographical references
رقم السجل
BIM-1184397
قاعدة معامل التأثير والاستشهادات المرجعية العربي "ارسيف Arcif"
أضخم قاعدة بيانات عربية للاستشهادات المرجعية للمجلات العلمية المحكمة الصادرة في العالم العربي
تقوم هذه الخدمة بالتحقق من التشابه أو الانتحال في الأبحاث والمقالات العلمية والأطروحات الجامعية والكتب والأبحاث باللغة العربية، وتحديد درجة التشابه أو أصالة الأعمال البحثية وحماية ملكيتها الفكرية. تعرف اكثر