TY - JOUR
T1 - Inhibiting crosstalk between MET signaling and mitochondrial dynamics and morphology
T2 - a novel therapeutic approach for lung cancer and mesothelioma
AU - Wang, Jiale
AU - Mirzapoiazova, Tamara
AU - Carol Tan, Yi Hung
AU - Pang, Ka Ming
AU - Pozhitkov, Alex
AU - Wang, Yingyu
AU - Wang, Yang
AU - Mambetsariev, Bolot
AU - Wang, Edward
AU - Nasser, Mohd W.
AU - Batra, Surinder K.
AU - Raz, Dan
AU - Reckamp, Karen
AU - Kulkarni, Prakash
AU - Zheng, Yanfang
AU - Salgia, Ravi
N1 - Funding Information:
This work was supported by the HHS | NIH | National Cancer Institute (NCI) P30CA033572.
Funding Information:
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award number P30CA033572. Additional financial support for this research was provided by Mirati Therapeutics Inc. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2018, © 2018 The Author(s). Published by Taylor & Francis.
PY - 2018/11/2
Y1 - 2018/11/2
N2 - The receptor tyrosine kinase MET is frequently involved in malignant transformation and inhibiting its activity in MET-dependent cancers is associated with improved clinical outcomes. Emerging evidence also suggests that mitochondria play an essential role in tumorigenesis and Dynamin Related Protein (DRP1), a key component of the mitochondrial fission machinery, has emerged as an attractive therapeutic target. Here, we report that inhibiting MET activity with the tyrosine kinase inhibitor MGCD516 attenuates viability, migration, and invasion of non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM) cell lines in vitro, and significantly retards tumor growth in vivo. Interestingly, MGCD516 treatment also results in altered mitochondrial morphology in these cell lines. Furthermore, inhibiting MET pharmacologically or knocking down its expression using siRNA, decreases DRP1 activity alluding to possible crosstalk between them in these two cancers. Consistently, a combination of MGCD516 and mdivi-1, a quinazolinone reported to inhibit mitochondrial fission, is more effective in attenuating proliferation of NSCLC and MPM cell lines than either drug alone. Considered together, the present study has uncovered a novel mechanism underlying mitochondrial regulation by MET that involves crosstalk with DRP1, and suggests that a combination therapy targeting both MET and DRP1 could be a novel strategy for NSCLC and MPM.
AB - The receptor tyrosine kinase MET is frequently involved in malignant transformation and inhibiting its activity in MET-dependent cancers is associated with improved clinical outcomes. Emerging evidence also suggests that mitochondria play an essential role in tumorigenesis and Dynamin Related Protein (DRP1), a key component of the mitochondrial fission machinery, has emerged as an attractive therapeutic target. Here, we report that inhibiting MET activity with the tyrosine kinase inhibitor MGCD516 attenuates viability, migration, and invasion of non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM) cell lines in vitro, and significantly retards tumor growth in vivo. Interestingly, MGCD516 treatment also results in altered mitochondrial morphology in these cell lines. Furthermore, inhibiting MET pharmacologically or knocking down its expression using siRNA, decreases DRP1 activity alluding to possible crosstalk between them in these two cancers. Consistently, a combination of MGCD516 and mdivi-1, a quinazolinone reported to inhibit mitochondrial fission, is more effective in attenuating proliferation of NSCLC and MPM cell lines than either drug alone. Considered together, the present study has uncovered a novel mechanism underlying mitochondrial regulation by MET that involves crosstalk with DRP1, and suggests that a combination therapy targeting both MET and DRP1 could be a novel strategy for NSCLC and MPM.
KW - DRP-1
KW - MET
KW - MGCD265
KW - Mdivi-1
KW - Non-small cell lung cancer
KW - malignant pleural mesothelioma
KW - mitochondrial dynamics
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U2 - 10.1080/15384047.2018.1472193
DO - 10.1080/15384047.2018.1472193
M3 - Article
C2 - 30311833
AN - SCOPUS:85054899580
VL - 19
SP - 1023
EP - 1032
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
SN - 1538-4047
IS - 11
ER -