Alteration in the sensitivity to crizotinib by Na+/H+ exchanger regulatory factor 1 is dependent to its subcellular localization in ALK-positive lung cancers.

Abstract

BACKGROUND:

Na+/H+ exchanger regulatory factor 1 (NHERF1) is an important scaffold protein participates in the modulation of a variety of intracellular signal pathways. NHERF1 was able to enhance the effects of chemo-drugs in breast and cervical cancer cells. Anaplastic lymphoma kinase (ALK) fusion mutations are validated molecules targeted therapy in lung cancers, where crizotinib can be used as the specific inhibitor to suppress tumor progression. However, due to the less frequent occurrence of ALK mutations and the complexity for factors to determine drug responses, the genes that could alter crizotinib sensitivity are unclear.

METHODS:

Both ALK-translocated and ALK-negative lung adenocarcinoma specimens in tissue sections were collected for immunohistochemistry. The possible mechanisms of NHERF1 and its role in the cell sensitivity to crizotinib were investigated using an ALK-positive and crizotinib-sensitive lung adenocarcinoma cell line H3122. Either a NHERF1 overexpression vector or agents for NHERF1 knockdown was used for crizotinib sensitivity measures, in association with cell viability and apoptosis assays.

RESULTS:

The expression level of NHERF1 in ALK-translocated NSCLC was significantly higher than that in other lung cancer tissues. NHERF1 expression in ALK positive lung cancer cells was regulated by ALK activities, and was in return able to alter the sensitivity to crizotinib. The function of NHERF1 to influence crizotinib sensitivity was depending on its subcellular distribution in cytosol instead of its nucleus localized form.

CONCLUSION:

Ectopically overexpressed NHERF1 could be a functional protein for consideration to suppress lung cancers. The determination of NHERF1 levels in ALK positive NSCLC tissues might be useful to predict crizotinib resistance, especially by distinguishing cytosolic or nuclear localized NHERF1 for the overexpressed molecules.

• Authors: Fenglian Yang, Mu Hu, Siyuan Chang, Jing Huang, Yang Si, Jinghui Wang, Shan Cheng, Wen G Jiang
• Journal: BMC cancer (BMC Cancer) Vol. 20 Issue 1 Pg. 202 (Mar 12 2020) ISSN: 1471-2407 [Electronic] England
• PMID: 32164629 (Publication Type: Journal Article)

Chemical References

• Phosphoproteins
• Sodium-Hydrogen Exchangers
• sodium-hydrogen exchanger regulatory factor
• Crizotinib
• ALK protein, human
• Anaplastic Lymphoma Kinase

Topics

• Anaplastic Lymphoma Kinase (genetics, metabolism)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Crizotinib (pharmacology)
• Cytosol (metabolism)
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lung Neoplasms (drug therapy, genetics, metabolism)
• Phosphoproteins (genetics, metabolism)
• Sodium-Hydrogen Exchangers (genetics, metabolism)
• Up-Regulation