Premium
Regulation of MAP kinase signaling by c‐Myc mediates the apoptotic response to vinca alkaloids
Author(s) -
Gristock Rachel A,
Wales Christina TK,
Jacobs Aaron T
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb158
Subject(s) - vinca , vinca alkaloid , apoptosis , vinblastine , biology , cancer research , pharmacology , cancer cell , cancer , biochemistry , vincristine , chemotherapy , genetics , cyclophosphamide
c‐Myc is a regulator of gene expression with dichotomous roles in cancer growth and viability. It is an oncogene that promotes cellular proliferation and is often over‐expressed in cancer. But c‐myc also sensitizes cancer cells to the actions of certain chemotherapeutics, including doxorubicin, cisplatin, and vinca alkaloids, among others, and is a potentially useful marker for predicting clinical responses to drug therapy. Our goal was to investigate the significance of c‐myc in mediating the apoptotic response to vinca alkaloids, and to determine the signaling pathways that relate c‐myc expression to the regulation of apoptosis. Experiments were performed in the colorectal cancer cell lines RKO and HCT‐116. Cells were transfected either with a negative control or c‐myc siRNA, then treated with vinca alkaloids (vinblastine, vincristine). Treatment with vinca alkaloids induced apoptosis in the range of 5–10 nM, as evidenced by caspase 3, 9 and PARP cleavage, and by fluorogenic assay of caspase‐3/7 activity. Vinca alkaloid treatment also caused robust JNK‐1/2 phosphorylation, which has been previously reported to promote apoptosis to these agents. Our data show that c‐myc is critical for JNK‐1/2 activation. Silencing c‐myc inhibits the phosphorylation of JNK‐1/2 on Thr183/Tyr185 in vinca alkaloid‐treated cells, and causes a corresponding reduction in drug‐induced apoptosis. The importance of JNK‐1/2 signaling was confirmed with the biochemical inhibitor SP600125, which attenuated apoptosis and increased the IC50 of vinca alkaloids by more than 20‐fold. Conversely to its effects on JNK‐1/2, silencing c‐myc enhanced the phosphorylation of ERK‐1/2, which promotes cell survival and resistance to apoptosis. Accordingly, inhibition of ERK‐1/2 with U0126 lowered the IC50 and restored apoptosis in c‐myc silenced cells. We therefore propose a model in which c‐myc facilitates JNK‐1/2 activation and suppresses ERK‐1/2, and demonstrate that when c‐myc expression is reduced, resistance to vinca alkaloid‐initiated apoptosis is acquired. Support or Funding Information Grant support: NIH Grant P20GM103466