Depleted aldehyde dehydrogenase 1A1 (ALDH1A1) reverses cisplatin resistance of human lung adenocarcinoma cell A549/DDP

Abstract

BackgroundCisplatin is the standard first‐line chemotherapeutic agent for the treatment of non‐small cell lung cancer (NSCLC). However, resistance to chemotherapy has been a major obstacle in the management of NSCLC. Aldehyde dehydrogenase 1A1 (ALDH1A1) overexpression has been observed in a variety of cancers, including lung cancer. The purpose of this study was to investigate the effect of ALDH1A1 expression on cisplatin resistance and explore the mechanism responsible.MethodsReverse transcriptase‐PCR was applied to measure the messenger RNA expression of ALDH1A1, while Western blot assay was employed to evaluate the protein expression of ALDH1A1, B‐cell lymphoma 2, Bcl‐2‐like protein 4, phospho‐protein kinase B (p‐AKT) and AKT. A short hairpin RNA was used to knockdown ALDH1A1 expression. A 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay was used to determine the effect of ALDH1A1 decrease on cell viability. The cell apoptotic rate was tested using flow cytometry assay.Results ALDH1A1 is overexpressed in cisplatin resistant cell line A549/DDP, compared with A549. ALDH1A1 depletion significantly decreased A549/DDP proliferation, increased apoptosis, and reduced cisplatin resistance. In addition, the phosphoinositide 3‐kinase (PI3K) / AKT pathway is activated in A549/DDP, and ALDH1A1 knockdown reduced the phosphorylation level of AKT. Moreover, the combination of ALDH1A1‐short hairpin RNA and PI3K/AKT pathway inhibitor LY294002 markedly inhibited cell viability, enhanced apoptotic cell death, and increased cisplatin sensitivity.ConclusionThese results suggest that ALDH1A1 depletion could reverse cisplatin resistance in human lung cancer cell line A549/DDP, and may act as a potential target for the treatment of lung cancers resistant to cisplatin.

Upregulation of ALDH1B1 promotes tumor progression in osteosarcoma

“…Recent studies have proved that ALDH1A1 is linked to drug resistance in chemotherapy [ 29 , 30 ]. With a similar role of ALDH1A1 in cancer, we also found that the inhibition of ALDH1B1 expression could increase the sensitivity of OS cells to chemotherapy (doxorubicin) (Figure 5A ), which were further supported by the inhibition abilities of colony forming and proliferation after ALDH1B1 silencing in the presence of doxorubicin (Figure 5D-5G ).…”

“…Abnormal expression and unbalanced biological activity of ALDHs are related with a variety of disease, including alcoholic liver disease, Sjögren–Larsson syndrome, type 2 hyperprolinemia, hyperammonemia, Parkinson's disease and cancers [ 12 ]. Referring to ALDH1 subfamily, recent studies have reported that ALDH1A1 and ALDH1A3 were significantly correlated to the poor overall survival and were considered as potential prognostic markers and therapeutic targets for patients [ 22 , 23 , 29 , 30 , 35 ]. ALDH1B1 is an enzyme to compose of ALDH1, a subfamily of ALDHs.…”

“…Furthermore, accumulating evidence suggests that cancer stem cell theory partially explains tumor progression and drug resistance and CSCs may contribute to chemoresistance by recreate the cellular heterogeneity of the parental tumor and [ 13 , 41 – 43 ]. As a number of ALDH1 family, ALDH1A1 was linked to drug resistance in chemotherapy through regulating CSCs [ 29 , 30 , 35 ]. The present study also showed that ALDH1B1 silencing could suppress the protein expressions of cancer stem cell markers.…”

Lycorine inhibits melanoma A375 cell growth and metastasis through the inactivation of the PI3K/AKT signaling pathway

“…Many reports have shown that the PI3K/Akt signaling pathway is involved in multiple cellular functions, including cell proliferation, apoptosis and invasion [21][22][23]. Thus, the PI3K/Akt pathway is usually regarded as one of the key target for various tumors treatment [24][25][26], including melanoma. Calero et al indicated that the combination of the HSP90 inhibitor 17AAG with the PI3K/mTOR inhibitor NVP-BEZ235 has a synergistic activity in decreasing melanoma cell growth, inducing apoptosis and targeting simultaneously the MAPK and PI3K/Akt/mTOR pathways [27].…”

Interferon-α Promotes the Expression of Cancer Stem Cell Markers in Oral Squamous Cell Carcinoma

“…It is the one of the first markers to identify HNSCC CSCs 12 . OSCC CSCs can be also isolated on the basis of functional activities of ALDH1A1, which contributes to chemotherapy resistance 13 . Recently, more and more therapies were investigated to target the CSC population.…”