Proteomic Profiling of Paclitaxel Treated Cells Identifies a Novel Mechanism of Drug Resistance Mediated by PDCD4.
Paclitaxel (PTX) is a widely used chemotherapeutic drug effective against numerous cancers. To elucidate cellular pathways targeted by PTX and identify novel mechanisms of PTX resistance, we used a SILAC based quantitative proteomic approach to evaluate global changes of cellular protein abundance in HeLa cells. We identified 347 proteins involved in a number of biological processes including spindle assembly, mitotic exit, and extracellular adhesion whose abundance changes upon PTX treatment. Notably, the tumor suppressor PDCD4 involved in translation suppression was down-regulated by PTX. We demonstrated that PDCD4 is a cell-cycle regulated protein and that changes in its abundance are sufficient to alter PTX sensitivity in multiple human cancer cell lines. Immunoprecipitation of PDCD4-RNA complexes and RT-PCR revealed that PDCD4 mediated PTX sensitivity acts through its interaction with mRNA of UBE2S, a ubiquitin K11 linkage conjugating enzyme critical for mitotic exit. Lastly, high levels of PDCD4 in lung cancer tissues are positively correlated with the longer overall survival time of the examined lung cancer patients with PTX involved adjuvant therapy. Therefore, our proteomic screen for paclitaxel targets not only provided novel insight into the cellular resistance to paclitaxel via the PDCD4-mitotic exit regulation axis, but also offered a predictive biomarker for paclitaxel-based personalized chemotherapy in the treatment of lung cancer.
†The Laboratory of Medical Genetics, Harbin Medical University, Harbin, China 150081.
Hui
H
Xu
‡Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, United States.
Noah
N
Dephoure
†The Laboratory of Medical Genetics, Harbin Medical University, Harbin, China 150081.
Huiying
H
Sun
†The Laboratory of Medical Genetics, Harbin Medical University, Harbin, China 150081.
Haiyuan
H
Zhang
†The Laboratory of Medical Genetics, Harbin Medical University, Harbin, China 150081.
Fangfang
F
Fan
†The Laboratory of Medical Genetics, Harbin Medical University, Harbin, China 150081.
Jiawei
J
Liu
†The Laboratory of Medical Genetics, Harbin Medical University, Harbin, China 150081.
Xuelian
X
Ning
§The Tumor Hospital, Harbin Medical University, Harbin, China 150081.
Shaochun
S
Dai
§The Tumor Hospital, Harbin Medical University, Harbin, China 150081.
Baogang
B
Liu
∥The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China 150001.
Min
M
Gao
†The Laboratory of Medical Genetics, Harbin Medical University, Harbin, China 150081.
Songbin
S
Fu
‡Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, United States.
Steven P
SP
Gygi
†The Laboratory of Medical Genetics, Harbin Medical University, Harbin, China 150081.
Chunshui
C
Zhou
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D002681:China; D003628:Database Management Systems; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D011485:Protein Binding; D040901:Proteomics; D016601:RNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D016019:Survival Analysis
D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins; D017239:Paclitaxel
PDCD4; UBE2S; cell cycle; drug sensitivity; lung cancer; paclitaxel; personalized chemotherapy; quantitative proteomics