title: Atypical protein kinase Cι (PKCι) promotes metastasis of esophageal squamous cell carcinoma by enhancing resistance to Anoikis via PKCι-SKP2-AKT pathway.
abstract: Protein kinase Cι (PKCι) is an atypical PKC isoform and participates in multiple aspects of the transformed phenotype in human cancer cells. We previously reported that frequent amplification and overexpression of PKCι were correlated with lymph node metastasis in primary esophageal squamous cell carcinomas (ESCC). In the present study, short interfering RNA-mediated silencing of PKCι revealed that this enzyme was required for cell migration, invasion, and resistance to anoikis. In vivo experiments showed that PKCι suppression decreased tumor growth in esophageal cancer xenografts and lung metastases in nude mice. At the molecular level, knockdown of PKCι in suspended ESCC cells caused a decrease in S-phase kinase-associated protein 2 (SKP2) that had been reported to promote resistance to anoikis via the PI3K/AKT pathway. AKT phosphorylation was abolished after PKCι suppression, but AKT activation could be refreshed by PKCι upregulation, suggesting that PKCι enhanced cell resistance to anoikis via the PKCι-SKP2-PI3K/AKT pathway. Addition of the proteasome inhibitor MG132 prevented the decrease of SKP2 in PKCι silenced cells, and polyubiquitin-SKP2 was elevated after PKCι depletion, showing that PKCι might regulate the expression of SKP2 through the ubiquitin-proteasome pathway in suspended cells. Furthermore, overexpression of SKP2 in PKCι-downregulated cells restored cell resistance to anoikis. Most importantly, PKCι expression significantly correlated with SKP2 in 133 ESCC tissues (P = 0.031). Taken together, our data show that PKCι promotes tumorigenicity and metastasis of human esophageal cancer and that SKP2 is a candidate downstream effector of PKCι signaling in ESCC.
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute Hospital, Chinese Academy of Medical Sciences, 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China.
authors.forename: Shu-Guang
authors.initials: SG
authors.lastname: Liu
authors.forename: Bo-Shi
authors.initials: BS
authors.lastname: Wang
authors.forename: Yan-Yi
authors.initials: YY
authors.lastname: Jiang
authors.forename: Tong-Tong
authors.initials: TT
authors.lastname: Zhang
authors.forename: Zhi-Zhou
authors.initials: ZZ
authors.lastname: Shi
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Yang
authors.forename: Xiao-Chun
authors.initials: XC
authors.lastname: Wang
authors.forename: De-Chen
authors.initials: DC
authors.lastname: Lin
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hai
authors.initials: H
authors.lastname: Yang
authors.forename: Yan
authors.initials: Y
authors.lastname: Cai
authors.forename: Qi-Min
authors.initials: QM
authors.lastname: Zhan
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Wang
mesh_terms: D000818:Animals; D023102:Anoikis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000556:secondary*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000201:enzymology / Q000473:pathology*; D020868:Gene Silencing; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000099293:Protein Kinase C-lambda
chemical_list: D007527:Isoenzymes; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D044786:S-Phase Kinase-Associated Proteins; D000099293:Protein Kinase C-lambda