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Expression of large tumour suppressor (LATS) kinases modulates chemotherapy response in advanced non-small cell lung
Susan Yang Luo1, Hoi-Hin Kwok1, Pan-Chyr Yang2
1Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China.
Background:
The Hippo signalling pathway plays an important role in regulating organ size and cell proliferation. Down-regulation of large tumour suppressor (LATS) protein homologs LATS1 or LATS2 has been found in lung cancer. LATS1 and LATS2 are the core components of the Hippo signalling pathway. LATS1 and LATS2 share some conserved structural features and exhibit redundant biological functions. The aim of this study was to dissect the interaction between these two homologs.
Methods:
In lung adenocarcinoma (AD) cells, protein expression of LATS1 and LATS2 were determined by western blotting; cell viability and apoptosis were measured by MTT and annexin V staining after treatment with cisplatin; subcellular distributions of LATS proteins were determined by immunofluorescence microscopy; LATS2 expression was modulated by shRNA-mediated knockdown or ectopic expression in cancer cell lines.
Results:
Manipulation of the expression of these two LATS kinases influenced cisplatin response in advanced lung AD cell lines. High LATS2-to-LATS1 ratio in H2023 cells was associated with cisplatin resistance, while low LATS2-to-LATS1 ratio in CL1-0 and CL83 cells was associated with sensitivity to cisplatin. Manipulating the LATS2-to-LATS1 ratio by LATS2 over-expression in CL1-0 and CL83 rendered them resistant to cisplatin treatment, whereas LATS2 knockdown in H2023 alleviated the LATS2-to-LATS1 ratio and sensitized cancer cells to cisplatin exposure.
Conclusions:
Our data suggested that the ratio of expression of LATS kinases played a role in the modulation of cisplatin sensitivity in advanced lung AD, and targeting of LATS proteins as a novel therapeutic strategy for lung AD deserves further investigation.
Insights
The ratio of large tumor suppressor (LATS) 1 and 2 proteins impacts lung cancer cell response to cisplatin. Modulating this LATS ratio may offer a new therapeutic strategy for lung adenocarcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- The Hippo signaling pathway is crucial for organ size and cell proliferation control.
- Down-regulation of large tumor suppressor (LATS) homologs, LATS1 and LATS2, is observed in lung cancer.
- LATS1 and LATS2 are key components of the Hippo pathway, sharing structural similarities and redundant functions.
Purpose of the Study:
- To investigate the interaction and functional relationship between LATS1 and LATS2 homologs.
- To determine the role of LATS1 and LATS2 in lung adenocarcinoma cell response to cisplatin treatment.
Main Methods:
- Western blotting to assess LATS1 and LATS2 protein expression in lung adenocarcinoma cells.
- MTT assays and Annexin V staining to measure cell viability and apoptosis after cisplatin treatment.
- Immunofluorescence microscopy for subcellular localization studies and shRNA/ectopic expression to modulate LATS2 levels.
Main Results:
- The ratio of LATS2 to LATS1 expression influenced cisplatin sensitivity in lung adenocarcinoma cell lines.
- A high LATS2/LATS1 ratio correlated with cisplatin resistance (H2023 cells), while a low ratio indicated sensitivity (CL1-0, CL83 cells).
- Over-expression of LATS2 conferred cisplatin resistance, whereas LATS2 knockdown sensitized cells to cisplatin.
Conclusions:
- The expression ratio of LATS1 and LATS2 kinases is a significant factor in modulating cisplatin sensitivity in advanced lung adenocarcinoma.
- Targeting LATS proteins represents a potential novel therapeutic strategy for lung adenocarcinoma that warrants further investigation.
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