Oncogenic Kras Promotes Chemotherapy-Induced Growth Factor Shedding via ADAM17

Abstract

Oncogenic mutations in Kras occur in 40% to 45% of patients with advanced colorectal cancer (CRC). We have previously shown that chemotherapy acutely activates ADAM17, resulting in growth factor shedding, growth factor receptor activation, and drug resistance in CRC tumors. In this study, we examined the role of mutant Kras in regulating growth factor shedding and ADAM17 activity, using isogenic Kras mutant (MT) and wild-type (WT) HCT116 CRC cells. Significantly higher levels of TGF-a and VEGF were shed from KrasMT HCT116 cells, both basally and following chemotherapy treatment, and this correlated with increased pErk (phosphorylated extracellular signal regulated kinase)1/2 levels and ADAM17 activity. Inhibition of Kras, MEK (MAP/ERK kinase)1/2, or Erk1/2 inhibition abrogated chemotherapy-induced ADAM17 activity and TGF-a shedding. Moreover, we found that these effects were not drug or cell line specific. In addition, MEK1/2 inhibition in KrasMT xenografts resulted in significant decreases in ADAM17 activity and growth factor shedding in vivo, which correlated with dramatically attenuated tumor growth. Furthermore, we found that MEK1/2 inhibition significantly induced apoptosis both alone and when combined with chemotherapy in KrasMT cells. Importantly, we found that sensitivity to MEK1/2 inhibition was ADAM17 dependent in vitro and in vivo. Collectively, our findings indicate that oncogenic Kras regulates ADAM17 activity and thereby growth factor ligand shedding in a MEK1/2/Erk1/2-dependent manner and that KrasMT CRC tumors are vulnerable to MEK1/2 inhibitors, at least in part, due to their dependency on ADAM17 activity.

α-Cyperone Inhibits PMA-Induced EPCR Shedding through PKC Pathway

“…31,32) Moreover, in HUVECs, it has been already reported that PKCα is involved in the regulation of VEGF 35) the one is mediated by TACE. 36,37) These results show that PKCα or PKCβ may be involved in the mechanism of TACE-mediated EPCR shedding induced by PMA, although further study is necessary. We have known that PKC translocation is a sign of PKC activation.…”

Secretome Signature Identifies ADAM17 as Novel Target for Radiosensitization of Non–Small Cell Lung Cancer

“…ADAM17 activity is also increased on cellular treatment with chemotherapeutic agents (40,41) and ADAM17 activation by the antimetabolite 5-FU and the topoisomerase I inhibitor SN-38 primarily occurs in a Kras-mutated background and via the MAP/ERK kinase pathway. Our results demonstrate that irradiation promotes ADAM17 activation, but in a furinmediated way and interestingly, in both Kras-wild-type (NCI-H125, CALU-3) and Kras-mutated NSCLC cell lines (A549, H460).…”

ADAM17: a molecular switch to control inflammation and tissue regeneration

“…32,No. 8 In addition to regulation at the transcriptional level, ADAM17 activity is controlled post-translationally in cancer cells by oncogenic ras, src and v-src, which leads to increased shedding of the ErbB ligand TGFa [32,33]. In addition, activated ADAM17 and subsequent ErbB transactivation can mediate resistance to chemotherapy [34].…”

“…Modification of disulfide Review Trends in Immunology August 2011, Vol. 32,No. 8 bonding was achieved by inactivation of extracellular protein disulfide isomerases (PDIs).…”

“…It is noteworthy that seven of eight amino acids (underlined) fit this Review Trends in Immunology August 2011, Vol. 32,No. 8 cleavage site preference in the cleavage site of TNFa between alanine and valine (SPLAQA -VRSSSRT).…”