aPKC inhibitors might be the sensitizer of chemotherapy and adoptive immunotherapy in the treatment of hASIPa-overexpressed breast cancer.
The atypical protein kinase C (aPKC) plays an important role in cell growth through the interaction with its substracts, including human ASIP (hASIP), which contains an aPKC phosphorylation site encoded by exon 17b of the gene. hASIP is expressed as numerous alternative splicing isoforms in the cells. Our results showed that hASIPa, an exon 17b-containing isoform of hASIP, is overexpressed in human breast cancer (HBC) MDA-MB-231, SK-BR-3, and MCF-7 cell lines and HBC specimens. The anticancer effects of 5-FU chemotherapy or adoptive immunotherapy and the synergic action of aPKC inhibitor against hASIPa-overexpressed HBC cells were tested. The results indicated that HBC MDA-MB-231 and SK-BR-3 cells were sensitive to 5-FU treatment in vitro. The combined treatment of aPKC inhibitor and 5-FU raised the anticancer activities against hASIPa-overexpressed HBC cells. The coculture of cytokine-induced killer (CIK) cells and autologous dendritic cells (DCs) with or without Her-2 peptide GP2 pulse created two new populations of effective immune-active T-cell populations called DC-modulated and cytokine-induced killer (DCIK) cells and peptide-DC-modulated and cytokine-induced killer (DCIK-P) cells. The DCIK cells showed cytotoxic activities on MDA-MB-231, SK-BR-3, and MCF-7 cells in MHC unrestricted manner. The DCIK-P cells possessed extra-enhanced cytotoxic activities against HLA-A2+/Her-2+ MDA-MB-231 cells in MHC restricted manner, but not for HLA-A2+/-/Her-2+ SK-BR-3 cells and HLA-A2+/Her-2+/- MCF-7 cells. The data suggested specific cytotoxic T-lymphocyte (CTL) activity of DCIK-P cells on MDA-MB-231 cells. The combined treatment of aPKC inhibitor with DCIK/DCIK-P cells further raised the anticancer activities against hASIPa-overexpressed HBC cells. The results demonstrated that the hASIPa/aPKC signaling pathway functions as an important regulator in the growth of HBC cells and aPKC inhibitor treatment showed the synergic activities on 5-FU or DCIK/DCIK-P cells adoptive immunotherapy against hASIPa-overexpressed HBC cells.
Department of Surgery, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai 200040, China.
Yi-ting
YT
Jin
Xue-xiang
XX
Ying
Yi-hong
YH
Hu
Qiang
Q
Zou
Hong-ying
HY
Wang
Yong-hua
YH
Xu
D054366:Agouti Signaling Protein / Q000235:genetics / Q000378:metabolism*; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D016219:Immunotherapy, Adoptive; D007694:Killer Cells, Natural / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008213:Lymphocyte Activation; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology; D014407:Tumor Cells, Cultured
C515182:ASIP protein, human; D054366:Agouti Signaling Protein; D000964:Antimetabolites, Antineoplastic; D016207:Cytokines; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; C115015:PKC-3 protein; D011493:Protein Kinase C; D005472:Fluorouracil