Abstract
TUSC2-defective gene expression is detected in the majority of lung cancers and is associated with worse overall survival. We analyzed the effects of TUSC2 re-expression on tumor cell sensitivity to the AKT inhibitor, MK2206, and explored their mutual signaling connections, in vitro and in vivo. TUSC2 transient expression in three LKB1-defective non-small cell lung cancer (NSCLC) cell lines combined with MK2206 treatment resulted in increased repression of cell viability and colony formation, and increased apoptotic activity. In contrast, TUSC2 did not affect the response to MK2206 treatment for two LKB1-wild type NSCLC cell lines. In vivo, TUSC2 systemic delivery, by nanoparticle gene transfer, combined with MK2206 treatment markedly inhibited growth of tumors in a human LKB1-defective H322 lung cancer xenograft mouse model. Biochemical analysis showed that TUSC2 transient expression in LKB1-defective NSCLC cells significantly stimulated AMP-activated protein kinase (AMPK) phosphorylation and enzymatic activity. More importantly, AMPK gene knockdown abrogated TUSC2-MK2206 cooperation, as evidenced by reduced sensitivity to the combined treatment. Together, TUSC2 re-expression and MK2206 treatment was more effective in inhibiting the phosphorylation and kinase activities of AKT and mTOR proteins than either single agent alone. In conclusion, these findings support the hypothesis that TUSC2 expression status is a biological variable that potentiates MK2206 sensitivity in LKB1-defective NSCLC cells, and identifies the AMPK/AKT/mTOR signaling axis as an important regulator of this activity.
Highlights
The complete loss or reduction of expression of the tumor suppressor gene TUSC2, known as FUS1, is detected in 82% of non-small cell lung cancers (NSCLC) and 100% of small cell lung cancers (SCLC) [1,2,3]
We found that TUSC2 transient expression, alone, caused a 10-15% increase of apoptosis in all three cell lines
In vivo tumor growth inhibition by TUSC2-MK2206 in a human TUSC2/LKB1-defective H322 lung cancer xenograft mouse model Previously, we have demonstrated the efficacy of intravenous systematic nanovesicle TUSC2 gene delivery in NSCLC mouse models [4,5,6,7]
Summary
The complete loss or reduction of expression of the tumor suppressor gene TUSC2 (tumor suppressor candidate 2), known as FUS1, is detected in 82% of non-small cell lung cancers (NSCLC) and 100% of small cell lung cancers (SCLC) [1,2,3]. TUSC2 gene product, a multifunctional protein, plays an important role in various cellular processes, including transcription, cell-cycle progression and apoptosis [4]. We have demonstrated that exogenous expression of TUSC2 in non-small cell lung carcinoma cells, deficient of its expression, significantly inhibited tumor cell growth [5,6]. Intravenous systemic delivery of TUSC2 to distant tumors, via intravenous N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTAP): cholesterol nanovesicles, suppressed tumor growth and progression in orthotopic human lung cancer xenograft models, and in a phase I clinical trial of stage 4 lung cancer patients who had progressed on chemotherapy [4,5,6,7]
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