Migration and invasion of drug-resistant lung adenocarcinoma cells are dependent on mitochondrial activity

Abstract

A small proportion of cancer cells have stem-cell-like properties, are resistant to standard therapy and are associated with a poor prognosis. The metabolism of such drug-resistant cells differs from that of nearby non-resistant cells. In this study, the metabolism of drug-resistant lung adenocarcinoma cells was investigated. The expression of genes associated with oxidative phosphorylation in the mitochondrial membrane was negatively correlated with the prognosis of lung adenocarcinoma. Because the mitochondrial membrane potential (MMP) reflects the functional status of mitochondria and metastasis is the principal cause of death due to cancer, the relationship between MMP and metastasis was evaluated. Cells with a higher MMP exhibited greater migration and invasion than those with a lower MMP. Cells that survived treatment with cisplatin, a standard chemotherapeutic drug for lung adenocarcinoma, exhibited increased MMP and enhanced migration and invasion compared with parental cells. Consistent with these findings, inhibition of mitochondrial activity significantly impeded the migration and invasion of cisplatin-resistant cells. RNA-sequencing analysis indicated that the expression of mitochondrial complex genes was upregulated in cisplatin-resistant cells. These results suggested that drug-resistant cells have a greater MMP and that inhibition of mitochondrial activity could be used to prevent metastasis of drug-resistant lung adenocarcinoma cells.

Mitochondrial miRNA Determines Chemoresistance by Reprogramming Metabolism and Regulating Mitochondrial Transcription

“…We also determined the ratio of mitochondrial and nuclear DNA in our cell models, revealing a ratio of 189 in CAL-27 cells and 391 in CAL-27-re cells ( Supplementary Fig. S2I), which is similar to the previous studies that cisplatin-resistant cells had a greater number of mitochondria than parental cells (32,33). Finally, we determined the amount of miR-2392 in the mitochondria, revealing 1.4 Â 10 3 and 6.5 Â 10 3 mitomiR-2392 per nDNA in CAL-27 and CAL-27-re cells, respectively; and 1.4 Â 10 3 /189 ¼ 7.4 per mtDNA in CAL-27 and 6.5 Â 10 3 /391 ¼ 16.6 per mtDNA in CAL-27-re; and a total amount of 1.4 Â 10 3 /2.3 Â 10 3 ¼ 60.9% in CAL-27 mitochondria whereas 6.5 Â 10 3 /9.6 Â 10 3 ¼ 67.7% in CAL-27-re mitochondria (Fig.…”

Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy

“…However, others have reported that the inhibition of respiratory complex I suppressed cancer metastasis and cancer growth in NSCLC [43,44]. A study revealed that cisplatin-resistant cells have increased complex I activity, MMP, and cellular ATP, implying that the activation of mitochondria leads to enhanced cell metastasis compared to parental cells [43]. In addition to complex I, the OXPHOS activity and expression levels of other respiratory complexes were upregulated in Ire cells ( Figure 4A,B).…”

“…Notably, both the activity and expression level of respiratory complex I were significantly increased in Ire cells (Figure 4). Numerous studies have attempted to understand the role of respiratory complex I in lung cancers [40][41][42][43][44]. It was demonstrated that 45% of lung cancers tested harbored mitochondrial DNA mutations affecting respiratory complexes, of which approximately 57% were in respiratory complex I, 18% in respiratory complex III, and 25% in respiratory complex IV [40].…”

“…Another study also described that the inhibition of complex I by knockdown or rotenone treatment enhanced cancer metastasis, tumor growth, and ROS generation in HeLa cells [42]. However, others have reported that the inhibition of respiratory complex I suppressed cancer metastasis and cancer growth in NSCLC [43,44]. A study revealed that cisplatin-resistant cells have increased complex I activity, MMP, and cellular ATP, implying that the activation of mitochondria leads to enhanced cell metastasis compared to parental cells [43].…”

Elevated Heme Synthesis and Uptake Underpin Intensified Oxidative Metabolism and Tumorigenic Functions in Non–Small Cell Lung Cancer Cells

“…In addition, components of OXPHOS complexes and markers of mitochondrial biogenesis are found to be highly predictive of reduced overall survival in patients with NSCLC (11). Likewise, another study showed that the expression of OXPHOS genes is negatively correlated with the prognosis of lung adenocarcinoma and that inhibition of OXPHOS activity impedes the migration and invasion of cisplatin-resistant cells (12). Strikingly, several recent studies showed that drugresistant cells of acute and chronic myeloid leukemia, breast cancer, lung cancer, and melanoma depend on OXPHOS and that targeting oxidative metabolism and mitochondrial respiration overcomes drug resistance in these cells (13)(14)(15).…”