AKT is indispensable for coordinating Par-4/JNK cross talk in p21 downmodulation during ER stress

Oncogenesis
R U RasoolA Goswami

Abstract

The double-edged role of p21 to command survival and apoptosis is emerging. The current investigation highlights ER stress-mediated JNK activation that plausibly triggers cell death by attenuating endogenous p21 level. Here, we demonstrated that ER stress activator 3-AWA diminishes the p21 levels in cancer cells by averting the senescent phenotype to commence G2/M arrest. In essence, the deceleration in p21 level occurs through ER stress/JNK/Caspase-3 axis via activation/induction of proapoptotic Par-4 and inhibition of AKT. The molecular dynamics studies identified important interactions, which may be responsible for the AKT inhibition and efficacy of 3-AWA towards AKT binding pocket. Interestingly, the p21 deceleration was rescued by incubating the cells with 3-AWA in the presence of an ER stress inhibitor, Salubrinal. Furthermore, we demonstrated that p21 expression decreases solitarily in Par-4+/+ MEFs; albeit, ER stress-induced JNK activation was observed in both Par-4+/+ and Par-4-/- MEFs. Par-4 knockdown or overexpression studies established that ectopic Par-4 along with ER stress are not sufficient to downregulate p21 in PC-3 cells but are adequate for DU-145 cells and that the ER stress inflicted activation of JNK, inh...Continue Reading

References

Sep 26, 1995·Proceedings of the National Academy of Sciences of the United States of America·G P DimriO Pereira-Smith
Aug 1, 1996·Genes & Development·K PolyakB Vogelstein
May 1, 2002·The EMBO Journal·Salvador MacipStuart A Aaronson
May 19, 2005·Cancer Research·Andrei L Gartel, Senthil K Radhakrishnan
Oct 8, 2005·Molecular Cell·Anindya GoswamiVivek M Rangnekar
Jul 20, 2006·Expert Opinion on Therapeutic Targets·Anja Jaeschke, Roger J Davis
Sep 6, 2006·EMBO Reports·Eva SzegezdiAfshin Samali
May 6, 2008·Bioorganic & Medicinal Chemistry Letters·Blaise LippaJoel Morris
Jun 24, 2008·Molecular Cell·Yongjie WeiBeth Levine
Jul 25, 2008·The EMBO Journal·Jayashree JoshiMaria T Diaz-Meco
May 15, 2009·Nature Reviews. Cancer·Tarek Abbas, Anindya Dutta
Jan 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Tommy AlainNahum Sonenberg
Jan 27, 2010·Oncogene·S ShimizuY Tsujimoto
Feb 12, 2011·Cellular and Molecular Life Sciences : CMLS·Dong-Oh MoonGi-Young Kim
Mar 3, 2011·Nature Cell Biology·Ira Tabas, David Ron
Apr 5, 2013·BJU International·Vincent Zecchini, David E Neal
Feb 12, 2015·Endocrine-related Cancer·Chrysovalantou MihailidouHippokratis Kiaris
Mar 21, 2015·Endocrine-related Cancer·Souren Mkrtchian
Aug 23, 2016·Molecular Informatics·Francesco Antonio GrecoAntonio Macchiarulo
Aug 29, 2016·Clinical & Experimental Metastasis·Reyaz Ur RasoolAnindya Goswami
Dec 20, 2016·Oncogenesis·D TongJ Jiang
May 1, 2016·Trends in Cancer·Hery UrraClaudio Hetz

❮ Previous
Next ❯

Citations

Aug 10, 2018·Chemical Biology & Drug Design·Shu-Yuan ChengElise Champeil
Jun 9, 2019·Breast Cancer Research and Treatment·Debasis NayakAnindya Goswami

❮ Previous
Next ❯

Methods Mentioned

BETA
co-immunoprecipitation
Transfection
transfections
FACS
confocal microscopy

Software Mentioned

Schrodinger suite
ImageJ
BD Diva
Graph Pad Prism
Desmond
SPSS

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.