NDLI: Inhibiting Glucosylceramide Synthase Sensitizes CML T315I Mutant to Bcr-Abl Inhibitor and Cooperatively Induces Glycogen Synthase Kinase-3-regulated Apoptosis

Please wait, while we are loading the content...

Inhibiting Glucosylceramide Synthase Sensitizes CML T315I Mutant to Bcr-Abl Inhibitor and Cooperatively Induces Glycogen Synthase Kinase-3-regulated Apoptosis

Content Provider	Semantic Scholar
Author	Huang, Wei-Ching Tsai, Cheng-Chieh Chen, Chia Ling Chen, Tsai-Yun Chen, Ya-Ping Lin, Yee-Shin Lu, Pei-Jung Tsao, Chiung-Wen Wang, Chi-Yun Cheng, Yi Lin Hsieh, Chia-Yuan Lin, Chiou Feng
Copyright Year	2011
Abstract	Inactivation of glycogen synthase kinase (GSK)-3 has been implicated in cancer progression. We previously showed abundance of inactive GSK-3 in human chronic myeloid leukemia (CML) cell line. CML is a hematopoietic malignancy caused by an oncogenic Bcr-Abl tyrosine kinase. In Bcr-Abl signaling, the role of GSK-3 is not well defined. Here we report that enforced expression of constitutively active GSK-3 reduced proliferation and increased Bcr-Abl-inhibition-induced apoptosis by nearly 1-fold. Bcr-Abl inhibition activated GSK-3 and GSK-3-dependent apoptosis. Inactivation of GSK-3 by Bcr-Abl activity is therefore confirmed. To re-activate GSK-3, we inhibited glucosylceramide synthase (GCS) to accumulate endogenous ceramide, a tumor-suppressor sphingolipid and a potent GSK-3 activator. We found silence of GCS and GCS inhibitor increased Bcr-Abl-inhibition-induced apoptosis by 4-fold and 10% respectively. Furthermore, GCS inhibitor sensitized the most clinical problematic drug-resistant CML T315I mutants to Bcr-Abl inhibitor GNF-2or imatinib-induced apoptosis by more than 5-fold. Combining GCS and Bcr-Abl inhibitors eliminated transplated-CML-T315I-mutants in vivo and dose-dependently sensitized primary cells from CML T315I patients to Bcr-Abl inhibitor-induced proliferation inhibition and apoptosis. The synergistic efficacy was Bcr-Abl-restricted and acted through GSK-3-mediated apoptosis. This study suggests a feasible novel anti-CML strategy by accumulating endogenous ceramide to re-activate GSK-3 and abrogate drug resistance.
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://ir.lib.ncku.edu.tw/bitstream/987654321/108272/2/Inhibiting+Glucosylceramide+Synthase+Sensitizes+CML+T315I+Mutant+to+Bcr-Abl+Inhibitor+and+Cooperatively+Induces+Glycogen+Synthase+Kinase-3-regulated+Apoptosis_Abstract.pdf
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in