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. 2019 May;17(5):4710-4716.
doi: 10.3892/ol.2019.10075. Epub 2019 Feb 26.

L-Lactate dehydrogenase B may be a predictive marker for sensitivity to anti-EGFR monoclonal antibodies in colorectal cancer cell lines

Ayumu Nagamine  1   2 , Takuya Araki  1   2 , Daisuke Nagano  1 , Mitsue Miyazaki  3 , Koujirou Yamamoto  1   2
Affiliations

L-Lactate dehydrogenase B may be a predictive marker for sensitivity to anti-EGFR monoclonal antibodies in colorectal cancer cell lines

Ayumu Nagamine et al. Oncol Lett. 2019 May.

Abstract

Recently, proteins derived from cancer cells have been widely investigated as biomarkers for predicting the efficacy of chemotherapy. In this study, to identify a sensitive biomarker for the efficacy of anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs), proteins derived from 6 colorectal cancer (CRC) cell lines with different sensitivities to cetuximab, an anti-EGFR mAb, were analyzed. Cytoplasmic and membrane proteins extracted from each CRC cell line were digested using trypsin and analyzed comprehensively using mass spectrometry. As a result, 148 and 146 peaks from cytoplasmic proteins and 363 and 267 peaks from membrane proteins were extracted as specific peaks for cetuximab-resistant and -sensitive CRC cell lines, respectively. By analyzing the proteins identified from the peptide peaks, cytoplasmic L-lactate dehydrogenase B (LDHB) was detected as a marker of cetuximab sensitivity, and it was confirmed that LDHB expression was increased in cetuximab-resistant CRC cell lines. Furthermore, LDHB expression levels were significantly upregulated with the acquisition of resistance to cetuximab in cetuximab-sensitive CRC cell lines. In conclusion, LDHB was identified as an important factor affecting cetuximab sensitivity using comprehensive proteome analysis for the first time.

Keywords: L-lactate dehydrogenase B; anti-epidermal growth factor receptor monoclonal antibodies; colorectal cancer; effect predictor; proteome.

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Figures

Figure 1.
Figure 1.
Candidate fragment ions derived from LDHB by MS fit analysis. LDHB chain sequence and six candidate fragment ions (m/z 720.40, 957.62, 754.38, 1011.57, 959.56 and 1176.60) derived from LDHB determined by conducting MS fit analysis using LC-TOF MS. No trypsin digestion mistakes in the candidate ions were detected.
Figure 2.
Figure 2.
Expression levels of an LDHB-specific sequence using LC-MS/MS in cytoplasmic proteins derived from six CRC cell lines. (A) LC-MS/MS chromatogram of the LDHB-specific sequence (SADTLWDIQK) in six CRC cell lines. (B) Peak area ratios of the LDHB-specific sequence (SADTLWDIQK) and the internal standard in six CRC cell lines. Data are presented as the mean ± standard deviation of triplicate experiments (One-way ANOVA, *P<0.05).
Figure 3.
Figure 3.
Changes in expression level of LDHB after acquisition of cetuximab resistance. Changes in LDHB expression levels in cytoplasmic proteins derived from cetuximab-sensitive cell lines (SW48 and C99) and cell lines that acquired cetuximab resistance (SW48R and C99R). Peak area ratios between the LDHB-specific sequence (SADTLWDIQK) and the internal standard in four CRC cell lines. Data are presented as the mean ± standard deviation of triplicate experiments (Mann-Whitney U test, *P<0.05).
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