Inhibiting crosstalk between MET signaling and mitochondrial dynamics and morphology: a novel therapeutic approach for lung cancer and mesothelioma

Jiale Wang, Tamara Mirzapoiazova, Yi Hung Carol Tan, Ka Ming Pang, Alex Pozhitkov, Yingyu Wang, Yang Wang, Bolot Mambetsariev, Edward Wang, Mohd W Nasser, Surinder Kumar Batra, Dan Raz, Karen Reckamp, Prakash Kulkarni, Yanfang Zheng, Ravi Salgia

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1023-1032
Number of pages10
JournalCancer Biology and Therapy
Volume19
Issue number11
DOIs
StatePublished - Nov 2 2018

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Mitochondrial Dynamics
Mesothelioma
Non-Small Cell Lung Carcinoma
Lung Neoplasms
Cell Line
Quinazolinones
Proto-Oncogene Proteins c-met
Dynamins
Neoplasms
Protein-Tyrosine Kinases
Small Interfering RNA
Mitochondria
Carcinogenesis
Therapeutics
Growth
Pharmaceutical Preparations
Malignant Mesothelioma
Proteins

Keywords

  • DRP-1
  • MET
  • MGCD265
  • Mdivi-1
  • Non-small cell lung cancer
  • malignant pleural mesothelioma
  • mitochondrial dynamics

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Inhibiting crosstalk between MET signaling and mitochondrial dynamics and morphology : a novel therapeutic approach for lung cancer and mesothelioma. / Wang, Jiale; Mirzapoiazova, Tamara; Carol Tan, Yi Hung; Pang, Ka Ming; Pozhitkov, Alex; Wang, Yingyu; Wang, Yang; Mambetsariev, Bolot; Wang, Edward; Nasser, Mohd W; Batra, Surinder Kumar; Raz, Dan; Reckamp, Karen; Kulkarni, Prakash; Zheng, Yanfang; Salgia, Ravi.

In: Cancer Biology and Therapy, Vol. 19, No. 11, 02.11.2018, p. 1023-1032.

Research output: Contribution to journalArticle

Wang, J, Mirzapoiazova, T, Carol Tan, YH, Pang, KM, Pozhitkov, A, Wang, Y, Wang, Y, Mambetsariev, B, Wang, E, Nasser, MW, Batra, SK, Raz, D, Reckamp, K, Kulkarni, P, Zheng, Y & Salgia, R 2018, 'Inhibiting crosstalk between MET signaling and mitochondrial dynamics and morphology: a novel therapeutic approach for lung cancer and mesothelioma', Cancer Biology and Therapy, vol. 19, no. 11, pp. 1023-1032. https://doi.org/10.1080/15384047.2018.1472193
Wang, Jiale ; Mirzapoiazova, Tamara ; Carol Tan, Yi Hung ; Pang, Ka Ming ; Pozhitkov, Alex ; Wang, Yingyu ; Wang, Yang ; Mambetsariev, Bolot ; Wang, Edward ; Nasser, Mohd W ; Batra, Surinder Kumar ; Raz, Dan ; Reckamp, Karen ; Kulkarni, Prakash ; Zheng, Yanfang ; Salgia, Ravi. / Inhibiting crosstalk between MET signaling and mitochondrial dynamics and morphology : a novel therapeutic approach for lung cancer and mesothelioma. In: Cancer Biology and Therapy. 2018 ; Vol. 19, No. 11. pp. 1023-1032.
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AU - Pang, Ka Ming

AU - Pozhitkov, Alex

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AU - Wang, Yang

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AU - Wang, Edward

AU - Nasser, Mohd W

AU - Batra, Surinder Kumar

AU - Raz, Dan

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AU - Salgia, Ravi

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