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

Landon J Inge; Jacqueline M Friel; Amanda L Richer; Aaron J Fowler; Timothy Whitsett; Michael A Smith; Nhan L Tran; Ross M Bremner

doi:10.1016/j.canlet.2014.06.011

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

Cancer Lett. 2014 Oct 1;352(2):187-95. doi: 10.1016/j.canlet.2014.06.011. Epub 2014 Jul 8.

Authors

Landon J Inge¹, Jacqueline M Friel², Amanda L Richer², Aaron J Fowler², Timothy Whitsett³, Michael A Smith², Nhan L Tran³, Ross M Bremner²

Affiliations

¹ Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States. Electronic address: [email protected].
² Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.
³ Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, AZ, United States.

PMID: 25011082
DOI: 10.1016/j.canlet.2014.06.011

Abstract

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.

Keywords: ER stress; LKB1; Lung cancer; Treatment; UPR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinase Kinases
AMP-Activated Protein Kinases
Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Brefeldin A / pharmacology
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / enzymology
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Deoxyglucose / pharmacology*
Dose-Response Relationship, Drug
Endoplasmic Reticulum / drug effects*
Endoplasmic Reticulum / metabolism
Endoplasmic Reticulum Chaperone BiP
Endoplasmic Reticulum Stress / drug effects*
Heat-Shock Proteins / metabolism
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / enzymology
Lung Neoplasms / genetics
Lung Neoplasms / pathology
Magnetic Resonance Imaging
Mice, Knockout
Mice, Transgenic
Protein Serine-Threonine Kinases / deficiency*
Protein Serine-Threonine Kinases / genetics
Proto-Oncogene Proteins p21(ras) / genetics
Reactive Oxygen Species / metabolism
Tunicamycin / pharmacology
Unfolded Protein Response / drug effects

Substances

Antineoplastic Agents
Endoplasmic Reticulum Chaperone BiP
Heat-Shock Proteins
Reactive Oxygen Species
Tunicamycin
Brefeldin A
Deoxyglucose
Protein Serine-Threonine Kinases
STK11 protein, human
Stk11 protein, mouse
AMP-Activated Protein Kinase Kinases
AMP-Activated Protein Kinases
Hras protein, mouse
Proto-Oncogene Proteins p21(ras)