title: Difference in protein expression profile and chemotherapy drugs response of different progression stages of LNCaP sublines and other human prostate cancer cells.
abstract: Androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, 80-90% of the patients who receive androgen ablation therapy ultimately develop recurrent tumors in 12-33 months after treatment with a median overall survival time of 1-2 years after relapse. LNCaP is a commonly used cell line established from a human lymph node metastatic lesion of prostatic adenocarcinoma. We previously established two relapsed androgen receptor (AR)-rich androgen-independent LNCaP sublines 104-R1 (androgen depleted for 12 months) and 104-R2 cells (androgen depleted for 24 months) from AR-positive androgen-dependent LNCaP 104-S cells. LNCaP 104-R1 and 104-R2 mimics the AR-positive hormone-refractory relapsed tumors in patients receiving androgen ablation therapy. Androgen treatment stimulates proliferation of 104-S cells, but causes growth inhibition and G1 cell cycle arrest in 104-R1 and 104-R2 cells. We investigated the protein expression profile difference between LNCaP 104-S vs. LNCaP 104-R1, 104-R2, PC-3, and DU-145 cells as well as examined the sensitivity of these prostate cancer cells to different chemotherapy drugs and small molecule inhibitors. Compared to 104-S cells, 104-R1 and 104-R2 cells express higher protein levels of AR, PSA, c-Myc, Skp2, BCL-2, P53, p-MDM2 S166, Rb, and p-Rb S807/811. The 104-R1 and 104-R2 cells express higher ratio of p-Akt S473/Akt, p-EGFR/EGFR, and p-Src/Src, but lower ratio of p-ERK/ERK than 104-S cells. PC-3 and DU-145 cells express higher c-Myc, Skp2, Akt, Akt1, and phospho-EGFR but less phospho-Akt and phospho-ERK. Overexpression of Skp2 increased resistance of LNCaP cells to chemotherapy drugs. Paclitaxel, androgen, and inhibitors for PI3K/Akt, EGFR, Src, or Bcl-2 seem to be potential choices for treatment of advanced prostate cancers. Our study provides rationale for targeting Akt, EGFR, Src, Bcl-2, and AR signaling as a treatment for AR-positive relapsed prostate tumors after hormone therapy.
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, County, Taiwan ; Translational Center for Glandular Malignancies, National Health Research Institutes, Miaoli, County, Taiwan.
authors.forename: Hui-Ping
authors.initials: HP
authors.lastname: Lin
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, County, Taiwan ; Translational Center for Glandular Malignancies, National Health Research Institutes, Miaoli, County, Taiwan ; National Institute of Cancer Research, National Health Research Institutes, Miaoli, County, Taiwan.
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Institute of Biotechnology, National Tsing Hua University, Hsinchu City, Taiwan.
authors.forename: Ping-Hsuan
authors.initials: PH
authors.lastname: Hsiao
authors.affiliation: Institute of Biotechnology, National Tsing Hua University, Hsinchu City, Taiwan.
authors.forename: Horng-Dar
authors.initials: HD
authors.lastname: Wang
authors.affiliation: Translational Center for Glandular Malignancies, National Health Research Institutes, Miaoli, County, Taiwan ; National Institute of Cancer Research, National Health Research Institutes, Miaoli, County, Taiwan.
authors.forename: Shih Sheng
authors.initials: SS
authors.lastname: Jiang
authors.affiliation: Department of Urology, Mackay Memorial Hospital, Taipei City, Taiwan.
authors.forename: Jong-Ming
authors.initials: JM
authors.lastname: Hsu
authors.affiliation: Department of Pediatrics, Mackay Memorial Hospital, Taipei City, Taiwan.
authors.forename: Wai-Tim
authors.initials: WT
authors.lastname: Jim
authors.affiliation: Department of Urology, Mackay Memorial Hospital, Taipei City, Taiwan.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Chen
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, County, Taiwan ; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, County, Taiwan.
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, County, Taiwan ; Translational Center for Glandular Malignancies, National Health Research Institutes, Miaoli, County, Taiwan ; Graduate Program for Aging, China Medical University, Taichung City, Taiwan ; Ph.D. Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung City, Taiwan.
authors.forename: Chih-Pin
authors.initials: CP
authors.lastname: Chuu
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008297:Male; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020543:Proteome; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014407:Tumor Cells, Cultured
chemical_list: D000728:Androgens; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; D020543:Proteome; D012333:RNA, Messenger; D011944:Receptors, Androgen; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D017430:Prostate-Specific Antigen