Title: Ribosomal Dysfunction Results in an Immunologic Susceptibility to Lung Cancer
1Ribosomal Dysfunction Results in an Immunologic
Susceptibility to Lung Cancer
- Stephanie Chang MD, Ryuji Higashikubo PhD, Saeed
Arefanian MD, Andrew Gelman PhD, Daniel Kreisel
MD, PhD, Alexander Krupnick MD - April 27th,2015
Department of Surgery Division of Cardiothoracic
Surgery
2Disclosures
3Susceptibility to Lung Cancer
Lung Cancer Resistant
- Previous work from our lab demonstrates natural
killer (NK) cells play a role in this process - Cancer Research 2012
Smoker with Bullous Emphysema
Lung Cancer Susceptible
Non-Smoker with Lung Cancer
4Expression of Sly 1 Correlates with Immunologic
Resistance to Lung Cancer
- X chromosome linked protein with unknown function
Sly1 380 AA 55 kD
Protein protein binding domains
5Objective
- The aim of this study was to determine the role
of Sly 1 in the susceptibility to lung cancer
development
6Expression of Sly 1 Correlates with Immunologic
Resistance to Lung Cancer
Humans
TNF a NK Cells
Lung Cancer Resistant
Lung Cancer Susceptible
Sly 1 Level by RT-PCR (normalized to
b-Actin/standardized patient)
7Expression of Sly 1 Correlates with Immunologic
Resistance to Lung Cancer
Human Sly 1 Function
TNF a NK Cells
Lung Cancer Resistant
Lung Cancer Susceptible
Sly 1 Level by RT-PCR (normalized to
b-Actin/standardized patient)
8Sly 1 Contributes to NK Cytotoxicity
Sly1- (knockout of the gene)
Wild-type littermates
9Sly 1 Contributes to NK Cytotoxicity
Sly1- (knockout of the gene)
Wild-type littermates
Activating Receptors Expression
10Sly 1 Expression Influences Lung Cancer Growth
Via NK Cells
Lewis Lung Carcinoma Tumor Growth
Control Group
Tumor Volume (mm3)
Days After Injection
11Sly 1 Contributes to NK Cytotoxicity of Lung
Cancer
12Sly 1 is a Ribosome Associated Protein
- Immunoprecipitation of WT and Sly 1 KO NK cell
lysates with anti-Sly 1 Ab to evaluate Sly 1
binding partners - No detection of signaling proteins from
activating receptors or cytokine pathways
13Sly 1 Affects mRNA levels
14How Could a Ribosomal Protein Impair Gene
Expression?
ribosome
- mRNA binding
- - No RNA-binding capacity
40s
mRNA
2) Ribosomal instability - Affects the
transcription factor E2F as a protective
mechanism
60s
15How Could a Ribosomal Protein Impair Gene
Expression?
Normal Cell
mRNA
E2F
promoter
ribosome
16How Could a Ribosomal Protein Impair Gene
Expression?
Ribosomal Stress Associated with Malignant
Transformation or Cell Stress
P
P
P
P
P
kinase
X
P
P
p53
P
Stop cellular proliferation and activation
p27
p21
17How Could a Ribosomal Protein Impair Gene
Expression?
Ribosomal Stress Associated with Malignant
Transformation or Cell Stress
P
P
P
P
P
kinase
X
P
P
p53
P
p27
p21
18High-dose IL-2 Can Stabilize the Ribosome
Lewis Lung Carcinoma Lysis in vitro
Activating Receptors Expression
At Rest
IL-2
At Rest
IL-2
19Conclusions
- Sly1 is a ribosomal protein that affects NK
ribosome stability at rest - Ribosomal stress is a sign of malignant
transformation which can destroy the cell or
decrease its activation/viability - Prior to our research, most X linked
ribosomopathies were considered severely
disabling but we now demonstrate that subtle
defects can manifest such as NK dysfunction and
immunologic susceptibility to lung cancer - IL2 can alleviate ribosomal stress and may be
useful in lung cancer immunotherapy
20Acknowledgements
- Thoracic Surgery Foundation for Research and
Education - NIH Ruth L Kirschstein NRSA
- Thoracic Immunology Lab
- Eberhard-Karls University Tuebingen
- Sandra Beer-Hammer, PhD
- Daniel Schall, PhD
21Questions?