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Cell Physiol Biochem. 2017;43(3):1126-1139. doi: 10.1159/000481754. Epub 2017 Oct 5.

Intensified Beclin-1 Mediated by Low Expression of Mir-30a-5p Promotes Chemoresistance in Human Small Cell Lung Cancer.

Yang X1, Bai F1, Xu Y2, Chen Y1,2, Chen L1,2.

Author information

1
Department of Medical Oncology, Jinling Hospital, Second Military Medical University, Nanjing, China.
2
Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.

Abstract

BACKGROUND/AIMS:

Although small cell lung cancer (SCLC) is sensitive to initial chemotherapy, patients experience tumor recurrence and metastasis, leading to treatment failure. Autophagy as a protective pattern for cell survival in the harsh environment plays an important role in chemoresistance. However, the role of Beclin-1, a key regulator of autophagy in the drug-resistance of SCLC cells is still poorly understood. In the current study, we focused on the effect and regulation of Beclin-1 in chemoresistance of SCLC cells.

METHODS:

We analyzed the levels of Beclin-1 in etoposide/cisplatin (EP) -resistant and -sensitive cell lines, as well as the relationship between Beclin-1 and patients' chemosensitivity. The function of Beclin-1 in chemoresistant SCLC cells in vitro was measured by MTT, WB, colony formation and flow cytometric analysis. Further rescue experiment was performed after co-transfected with siBeclin-1 and miR-30a mimics or inhibitor.

RESULTS:

Beclin-1 was upregulated in drug-resistant cells and patients with lower sensitivity to etoposide/cisplatin therapy. Downregulated Beclin-1 attenuated drug sensitivity and colony formation ability of chemoresistant cells. Moreover, inhibition of Beclin-1 resulted in a dramatic decline of autophagy and increase of apoptosis in drug-resistant cells, accompanied by a remarkable reduction in S phase and a raise in G2/M phase of cell cycle. The transfection with miR-30a-5p mimics exhibited an opposite effect. In addition, inhibition of Beclin-1 could partly reverse the effect induced by miR-30a-5p suppression in drug-sensitive cells.

CONCLUSION:

Beclin-1 regulated by miR-30a-5p plays a notable role in the drug-resistance of SCLC. Inhibition of Beclin-1 by induction of miR-30a-5p may improve the therapeutic outcome via resensitizing the drug-resistant cells to chemotherapy in SCLC.

KEYWORDS:

Autophagy; Beclin-1; Chemoresistance; MiR-30a-5p; Small cell lung cancer

PMID:
28977798
DOI:
10.1159/000481754
[Indexed for MEDLINE]
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