Molecular targeting of cell-permeable peptide inhibits pancreatic ductal adenocarcinoma cell proliferation

Sato, Sunao; Nakamura, Tõru; Katagiri, Toyomasa; Tsuchikawa, Takahiro; Kubota, Toshihiro; Hontani, Kouji; Takahashi, Mitsuru; Inoko, Kazuho; Takano, Hironobu; Abe, Hiroki; Takeuchi, Shintaro; Ono, Masato; Kuwabara, Shota; Umemoto, Kazufumi; Suzuki, Tomohiro; Sato, Osamu; Nakamura, Yusuke; Hirano, Satoshi

doi:10.18632/oncotarget.21939

Cited by 5 publications

(8 citation statements)

References 34 publications

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“…Previous studies showed that C16orf74 interacted to PPP3CA (calcineurin: CN) and was important for proliferation and invasion of PDAC (6,11). This study demonstrated that C16orf74 might be the molecule that connected the integrin signal and CN signal.…”

Section: Discussionmentioning

confidence: 52%

“…Paraffin-embedded sections were used for IHC staining. Same protocol was followed as our previous study (11). Finally, the sections were counterstained with hematoxylin.…”

Section: Ihc Stainingmentioning

confidence: 99%

“…Same protocol was followed as our previous study (11). At least three randomly selected fields were investigated and invaded cells were counted at Â100 magnifications.…”

Section: Matrigel Invasion Assaymentioning

confidence: 99%

“…With the functional analysis of C16orf74, previously, we have demonstrated that C16orf74 interacts with the catalytic subunit alpha of protein phosphatase 3 (PPP3CA) as well as the calcineurin (CN) isozyme. This interaction promotes proliferation and invasion of PDAC cells (6,11). However, the pathophysiologic functional analysis of C16orf74 is unclear.…”

Section: Introductionmentioning

confidence: 99%

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Role of Dimerized C16orf74 in Aggressive Pancreatic Cancer: A Novel Therapeutic Target

Kubota

Nakamura

Tsuda

et al. 2020

Molecular Cancer Therapeutics

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Over the past 30 years, the therapeutic outcome for pancreatic ductal adenocarcinoma (PDAC) has remained stagnant due to the lack of effective treatments. We performed a genome-wide analysis to identify novel therapeutic targets for PDAC. Our analysis showed that Homo sapiens chromosome 16 open reading frame 74 (C16orf74) was upregulated in most patients with PDAC and associated with poor prognosis. Previously, we demonstrated that C16orf74 interacts with the catalytic subunit alpha of protein phosphatase 3 and plays an important role in PDAC invasion. However, the pathophysiologic function of C16orf74 is still unclear. In this study, through the analysis of C16orf74 interaction, we demonstrate a new strategy to inhibit the growth and invasion of PDAC. C16orf74 exists in the homodimer form under the cell membrane and binds integrin aVb3 and is also involved in invasion by activating Rho family (Rac1) and MMP2. Considering that this dimeric form was found to be involved in the function of C16orf74, we designed an 11R-DB (dimer block) cell-permeable dominantnegative peptide that inhibits the dimer form of C16orf74. 11R-DB suppressed invasion and proliferation of PDAC cell lines by inhibiting phosphorylation of Akt and mTOR and also by inactivation of MMP2. 11R-DB also showed antitumor effects in an orthotopic xenograft model and peritoneal metastasis model. Thus, this study demonstrates that dimerized C16orf74, present in the cell membrane, is involved in pancreatic cancer invasion and proliferation. In addition, the C16orf74 dimer block cell-permeable peptide (11R-DB) has a potent therapeutic effect on PDAC in vitro and in vivo.

show abstract

Section: Discussionmentioning

confidence: 52%

“…Paraffin-embedded sections were used for IHC staining. Same protocol was followed as our previous study (11). Finally, the sections were counterstained with hematoxylin.…”

Section: Ihc Stainingmentioning

confidence: 99%

“…Same protocol was followed as our previous study (11). At least three randomly selected fields were investigated and invaded cells were counted at Â100 magnifications.…”

Section: Matrigel Invasion Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Role of Dimerized C16orf74 in Aggressive Pancreatic Cancer: A Novel Therapeutic Target

Kubota

Nakamura

Tsuda

et al. 2020

Molecular Cancer Therapeutics

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“…The membrane-permeable arginine-rich peptide could facilitate efficiently the nonspecific uptake of peptides into cells and is considered to be a good peptide delivery system [30] , [31] . To investigate the biological significance of GALNT6-mediated ER-α O-glycosylation, we designed two cell membrane–permeable peptides corresponding to the S573 O-glycosylation site in the F domain: one with the wild-type sequence and the other with the substitution of this serine residue to proline.…”

Section: Discussionmentioning

confidence: 99%

Critical Role of Estrogen Receptor Alpha O-Glycosylation by N-Acetylgalactosaminyltransferase 6 (GALNT6) in Its Nuclear Localization in Breast Cancer Cells

et al. 2018

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Alteration of protein O-glycosylation in various human cancers including breast cancer is well known, but molecular roles of their aberrant glycosylations on cancer have not been fully understood. We previously reported critical roles of polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6 or GalNAc-T6) that was upregulated in a great majority of breast cancer tissues. Here we further report O-glycosylation of estrogen receptor alpha (ER-α) by GALNT6 and the significant role of its nuclear localization in breast cancer cells. Knockdown of GALNT6 expression in two breast cancer cell lines, T47D and MCF7, in which both ER-α and GALNT6 were highly expressed, by small interfering RNA could significantly attenuate expression of ER-α. Immunocytochemical analysis clearly demonstrated the drastic decrease of ER-α protein in the nucleus of these cancer cells. Accordingly, the downstream genes of the ER-α pathway such as MYC, CCND1, and CTSD were significantly downregulated. We confirmed GALNT6-dependent ER-α O-glycosylation and identified O-glycosylation of S573 in an F domain of ER-α by GALNT6 through LC-MS/MS analysis. We also obtained evidences showing that the glycosylation of ER-α at S573 by GALNT6 is essential for protein stability and nuclear localization of ER-α in breast cancer cells. Furthermore, we designed cell membrane–permeable peptides including the O-glycosylation site and found a significant decrease of the cell viability of breast cancer cells by treatment of these peptides in a GALNT6 expression–dependent manner. Our study suggests that targeting the GALNT6 enzymatic activity as well as the GALNT6/ER-α interaction could be a promising therapeutic approach to ER-α–positive breast cancer patients.

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Construction and Evaluation of an M2 Macrophage-Related Prognostic Model for Colon Cancer

Ji,

Chen,

Zhang

et al. 2023

Appl Biochem Biotechnol

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Molecular targeting of cell-permeable peptide inhibits pancreatic ductal adenocarcinoma cell proliferation

Cited by 5 publications

References 34 publications

Role of Dimerized C16orf74 in Aggressive Pancreatic Cancer: A Novel Therapeutic Target

Role of Dimerized C16orf74 in Aggressive Pancreatic Cancer: A Novel Therapeutic Target

Critical Role of Estrogen Receptor Alpha O-Glycosylation by N-Acetylgalactosaminyltransferase 6 (GALNT6) in Its Nuclear Localization in Breast Cancer Cells

Construction and Evaluation of an M2 Macrophage-Related Prognostic Model for Colon Cancer

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