Role of RAF/MEK/ERK pathway, p-STAT-3 and Mcl-1 in sorafenib activity in human pancreatic cancer cell lines.
Sorafenib is a multikinase inhibitor that has shown promising therapeutic results in different tumor histotypes, both as a single agent or in combination with other treatments. We analyzed the in vitro activity of sorafenib in pancreatic cancer, one of the most lethal and chemo-radio-resistant tumors, using four human pancreatic cancer cell lines (t3m4, Capan 1, Capan 2, and MiaPaca 2), characterized by different K-ras gene status and RAF/MEK/ERK profile. Sorafenib exerted a strong anti-proliferative effect independently of RAS/RAF/MEK/ERK and induced various degrees of apoptosis in the cell lines. The mechanisms involved were explored in detail in t3m4 and Capan 1, in which sorafenib induced the highest and lowest levels of apoptosis, respectively. In t3m4, the RAF/AKT/STAT-3 rather than the RAF/MEK/ERK pathway was involved, whereas in Capan 1 cells there was a strong decrease in pMEK and pERK which was not accompanied by an important reduction in RAF, AKT, and STAT-3 proteins or in their phosphorylation. Moreover, U0126-induced MEK inhibition did not induce apoptosis in any cell line, reinforcing the hypothesis of a MEK/ERK-independent mechanism of sorafenib activity. Mcl-1 appears to play a crucial role in sorafenib-induced apoptosis. In fact, both protein and mRNA were downregulated in t3m4 and upregulated in Capan 1, in which siRNA-induced silencing resulted in the same level of apoptosis as observed in t3m4. Our results show that sorafenib exerts anti-proliferative and pro-apoptotic activity in pancreatic cancer cells. Used singly or in combination with other drugs, it could therefore represent valid treatment for pancreatic cancer.
Ulivi
Paola
P
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy.
Arienti
Chiara
C
Amadori
Dino
D
Fabbri
Francesco
F
Carloni
Silvia
S
Tesei
Anna
A
Vannini
Ivan
I
Silvestrini
Rosella
R
Zoli
Wainer
W
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D011905:Genes, ras; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009536:Niacinamide / Q000031:analogs & derivatives; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010671:Phenylurea Compounds; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000077157:Sorafenib; D013997:Time Factors; D048490:raf Kinases / Q000378:metabolism*
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D009536:Niacinamide; D000077157:Sorafenib; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases