LKB1 inactivation sensitizes non-small cell lung cancer to pharmacological aggravation of ER stress.

Autor: Inge LJ; Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States. Electronic address: landon.inge@dignityhealth.org., Friel JM; Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States., Richer AL; Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States., Fowler AJ; Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States., Whitsett T; Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, AZ, United States., Smith MA; Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States., Tran NL; Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, AZ, United States., Bremner RM; Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2014 Oct 01; Vol. 352 (2), pp. 187-95. Date of Electronic Publication: 2014 Jul 08.
DOI: 10.1016/j.canlet.2014.06.011
Abstrakt: Five-year survival rates for non-small cell lung cancer (NSCLC) have seen minimal improvement despite aggressive therapy with standard chemotherapeutic agents, indicating a need for new treatment approaches. Studies show inactivating mutations in the LKB1 tumor suppressor are common in NSCLC. Genetic and mechanistic analysis has defined LKB1-deficient NSCLC tumors as a phenotypically distinct subpopulation of NSCLC with potential avenues for therapeutic gain. In expanding on previous work indicating hypersensitivity of LKB1-deficient NSCLC cells to 2-deoxy-D-glucose (2DG), we find that 2DG has in vivo efficacy in LKB1-deficient NSCLC using transgenic murine models of NSCLC. Deciphering of the molecular mechanisms behind this phenotype reveals that loss of LKB1 in NSCLC cells imparts increased sensitivity to pharmacological compounds that aggravate ER stress. In comparison to NSCLC cells with functional LKB1, treatment of NSCLC cells lacking LKB1 with the ER stress activators (ERSA), tunicamycin, brefeldin A or 2DG, resulted in aggravation of ER stress, increased cytotoxicity, and evidence of ER stress-mediated cell death. Based upon these findings, we suggest that ERSAs represent a potential treatment avenue for NSCLC patients whose tumors are deficient in LKB1.
(Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)
Databáze: MEDLINE
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