Therapeutic effect of anti CEACAM6 monoclonal antibody against lung adenocarcinoma by enhancing anoikis sensitivity

Hong, Kwon Pyo; Shin, Mi Hyang; Yoon, Shin-Eui; Ji, Gil Yong; Moon, Yoo Ri; Lee, Ok-Jun; Choi, Song‐Yi; Lee, Yong Moon; Koo, Ji Hae; Lee, Ho-Chang; Lee, Geon Kook; Kim, Seung Ryul; Lee, Ki Hyeong; Han, Hye‐Suk; Choe, Kang Hyeon; Lee, Ki Man; Hong, Jong-Phil; Kim, Si-Wook; Yi, Jae Hyuk; Ji, Hyeong-Jin; Kim, Yun-Bae; Song, Hyung Geun

doi:10.1016/j.biomaterials.2015.07.012

Cited by 30 publications

(33 citation statements)

References 38 publications

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“…Our GO analysis also revealed altered expression of CEACAM1, which is involved in cell motility and localization (Supplemental Table ST1). Since two similar genes, CEACAM6 and CEACAM7, have been implicated in lung cancer [61, 62], we also examined the levels of these genes. As shown in Fig 4A, suppression of Pard3a significantly decreased the mRNA levels of APOE, CCL2, IL12A, SFRP5, SOD2, and VCAM1 while inducing mRNA levels of CEACAM1, CEACAM6, FGFR2, FN1, IGFBP1, MAP3K1, MMP7, NOX1, PAX7, and VCAN.…”

Section: Resultsmentioning

confidence: 99%

Downregulation of PKCζ/Pard3/Pard6b is responsible for lung adenocarcinoma cell EMT and invasion

Zhou

Dai

Chen

et al. 2017

Cellular Signalling

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Atypical protein kinase C ζ (PKCζ) forms an apico-basal polarity complex with Partitioning Defective (Pard) 3 and Pard6 to regulate normal epithelial cell apico-basolateral polarization. The dissociation of the PKCζ/Pard3/Pard6 complex is essential for the disassembly of the tight/adherens junction and epithelial-mesenchymal transition (EMT) that is critical for tumor spreading. Loss of cell polarity and epithelial organization is strongly correlated with malignancy and tumor progression in some other cancer types. However, it is unclear whether the PKCζ/Pard3/Pard6 complex plays a role in the progression of non-small-cell lung cancer (NSCLC). We found that hypoxia downregulated the PKCζ/Pard3/Pard6 complex, correlating with induction of lung cancer cell migration and invasion. Silencing of the PKCζ/Pard3/Pard6 polarity complex components induced lung cancer cell EMT, invasion, and colonization in vivo. Suppression of Pard3 was associated with altered expression of genes regulating wound healing, cell apoptosis/death and cell motility, and particularly upregulation of MAP3K1 and fibronectin which are known to contribute to lung cancer progression. Human lung adenocarcinoma tissues expressed less Pard6b and PKCζ than the adjacent normal tissues and in experimental mouse lung adenocarcinoma, the levels of Pard3 and PKCζ were also decreased. In addition, we showed that a methylation locus in the gene body of Pard3 is positively associated with the expression of Pard3 and that methylation of the Pard3 gene increased cellular sensitivity to carboplatin, a common chemotherapy drug. Suppression of Pard3 increased chemoresistance in lung cancer cells. Together, these results suggest that reduced expression of PKCζ/Pard3/Pard6 contributes to NSCLC EMT, invasion, and chemoresistance.

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Section: Resultsmentioning

confidence: 99%

Downregulation of PKCζ/Pard3/Pard6b is responsible for lung adenocarcinoma cell EMT and invasion

Zhou

Dai

Chen

et al. 2017

Cellular Signalling

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“…Combination immunotherapy that involves a tumor-antigen-targeting antibody, recombinant interleukin-2, an anti-programmed death-1 antibody, and a powerful T-cell vaccine is capable of eradicating large established tumors in mice 30 . The CEACAM6 antibody and vaccine significantly inhibited tumor development 28 , 31 , 32 . These observations suggest that combination immunotherapy and antibodies against CEACAM6 and CEA may be effective treatments for GC.…”

Section: Discussionmentioning

confidence: 99%

Dual role of carcinoembryonic antigen-related cell adhesion molecule 6 expression in predicting the overall survival of gastric cancer patients

Zang

Cao

et al. 2017

Sci Rep

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Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is a member of the glycosylphosphatidylinositol-linked immunoglobulin superfamily that is implicated in many human cancers. Here, we aimed to investigate the role of CEACAM6 expression in predicting the overall survival (OS) in gastric cancer (GC). The impact of CEACAM6 on the survival of patients with GC (n = 876) was assessed using an online Kaplan-Meier plotter. Findings were validated using the OS data of patients (n = 160) recruited from Ruijin Hospital. We found that high CEACAM6 expression was associated with a better OS in early-stage or well-differentiated GC, or who were treated without 5-fluorouracil (5-FU). Conversely, high CEACAM6 expression was associated with a poor OS in advanced-stage GC, poorly differentiated tumors, or who were treated with 5-FU. Furthermore, CEACAM6 may serve as a better marker for predicting OS in GC than CEA. In addition, CEACAM6 overexpression in GC cells increased apoptotic resistance to 5-FU. Moreover, CEACAM6 induced cluster of differentiation 4- and 8-positive lymphocytes were detected in early-stage GC. In conclusion, CEACAM6 plays a contradictory role in predicting the OS in GC. In early-stage GC, high CEACAM6 expression is associated with improved OS. However, in advanced-stage GC, high CEACAM6 expression is associated with a poor OS.

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“…Splenocytes from immunized mice were fused with SP2/0 mouse myeloma cell line (ATCC, #CRL-1581). Finally, P5 mAb was established through repeating screenings and limiting dilutions 3 times [ 16 ] .…”

Section: Methodsmentioning

confidence: 99%

Novel monoclonal antibody against beta 1 integrin enhances cisplatin efficacy in human lung adenocarcinoma cells

Kim¹,

Cho²,

Hong³

et al. 2016

J Biomed Res

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The use of anti-beta 1 integrin monoclonal antibody in lung cancer treatment has proven beneficial. Here, we developed a novel monoclonal antibody (mAb), called P5, by immunizing mice with human peripheral blood mononuclear cells (PBMC). Its anti-tumor effect is now being tested, in a clinical phase III trial, in combinatorial treatments with various chemical drugs. To confirm that P5 indeed binds to beta 1 integrin, cell lysates were immunoprecipitated with commercial anti-beta 1 integrin mAb (TS2/16) and immunoblotted against P5 to reveal a 140 kDa molecular weight band, as expected. Immunoprecipitation with P5 followed by LC/MS protein sequence analysis further verified P5 antigen to be beta 1 integrin. Cisplatin treatment upregulated cell surface expression of beta 1 integrin in A549 cells, while causing inhibition of cell growth. When cells were co-treated with different concentrations of P5 mAb, the cisplatin-mediated inhibitory effect was enhanced in a dose-dependent manner. Our findings show that a combinatorial treatment of P5 mAb and cisplatin in A549 cells resulted in a 30% increase in apoptosis, compared to baseline, and significantly more when compared to either the cisplatin or P5 alone group. The entire peptide sequences in CDR from variable region of Ig heavy and light chain gene for P5 mAb are also disclosed. Together, these results provide evidence of the beneficial effect of P5 mAb in combinatorial treatment of human lung adenocarcinoma.

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Therapeutic effect of anti CEACAM6 monoclonal antibody against lung adenocarcinoma by enhancing anoikis sensitivity

Cited by 30 publications

References 38 publications

Downregulation of PKCζ/Pard3/Pard6b is responsible for lung adenocarcinoma cell EMT and invasion

Downregulation of PKCζ/Pard3/Pard6b is responsible for lung adenocarcinoma cell EMT and invasion

Dual role of carcinoembryonic antigen-related cell adhesion molecule 6 expression in predicting the overall survival of gastric cancer patients

Novel monoclonal antibody against beta 1 integrin enhances cisplatin efficacy in human lung adenocarcinoma cells

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