Sorafenib and pemetrexed toxicity in cancer cells is mediated via SRC-ERK signaling.
The present studies sought to further understand how the anti-folate pemetrexed and the multi-kinase inhibitor sorafenib interact to kill tumor cells. Sorafenib activated SRC, and via SRC the drug combination activated ERK1/2. Expression of dominant negative SRC or dominant negative MEK1 abolished drug-induced ERK1/2 activation, together with drug-induced autophagy, acidic lysosome formation, and tumor cell killing. Protein phosphatase 2A is an important regulator of the ERK1/2 pathway. Fulvestrant resistant MCF7 cells expressed higher levels of the PP2A inhibitor SET/I2PP2A, had lower endogenous PP2A activity, and had elevated basal ERK1/2 activity compared with their estrogen dependent counterparts. Overexpression of I2PP2A blocked drug-induced activation of ERK1/2 and tumor cell killing. PP2A can be directly activated by ceramide and SET/I2PP2A can be inhibited by ceramide. Inhibition of the de novo ceramide synthase pathway blocked drug-induced ceramide generation, PP2A activation and tumor cell killing. Collectively these findings demonstrate that ERK1/2 plays an essential role downstream of SRC in pemetrexed and sorafenib lethality and that PP2A plays an important role in regulating this process.
Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, USA.
M Danielle
MD
Bareford
Hossein A
HA
Hamed
Jeremy
J
Allegood
Nichola
N
Cruickshanks
Andrew
A
Poklepovic
Margaret A
MA
Park
Besim
B
Ogretmen
Sarah
S
Spiegel
Steven
S
Grant
Paul
P
Dent
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D004357:Drug Synergism; D011992:Endosomes / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D005971:Glutamates / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System; D009536:Niacinamide / Q000031:analogs & derivatives; D000068437:Pemetrexed; D010671:Phenylurea Compounds; D054648:Protein Phosphatase 2 / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D034622:RNA Interference; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D000077157:Sorafenib; D019061:src-Family Kinases / Q000378:metabolism*
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D005971:Glutamates; D010671:Phenylurea Compounds; D011725:Pyridines; D000068437:Pemetrexed; D009536:Niacinamide; D006147:Guanine; D000077157:Sorafenib; D020797:Receptor, Platelet-Derived Growth Factor beta; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D054648:Protein Phosphatase 2