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Microtubule affinity-regulating kinase 2 is associated with DNA damage response and cisplatin resistance in non-small cell lung cancer.

Authors
  • Hubaux, Roland
  • Thu, Kelsie L
  • Vucic, Emily A
  • Pikor, Larissa A
  • Kung, Sonia H Y
  • Martinez, Victor D
  • Mosslemi, Mitra
  • Becker-Santos, Daiana D
  • Gazdar, Adi F
  • Lam, Stephen
  • Lam, Wan L
Type
Published Article
Journal
International Journal of Cancer
Publisher
Wiley (John Wiley & Sons)
Publication Date
Nov 01, 2015
Volume
137
Issue
9
Pages
2072–2082
Identifiers
DOI: 10.1002/ijc.29577
PMID: 25907283
Source
Medline
Keywords
License
Unknown

Abstract

Microtubule affinity-regulating kinases (MARKs) are involved in several cellular functions but few studies have correlated MARK kinase expression with cancer, and none have explored their role in lung cancer. In this study, we identified MARK2 as frequently disrupted by DNA hypomethylation and copy gain, resulting in concordant overexpression in independent lung tumor cohorts and we demonstrate a role for MARK2 in lung tumor biology. Manipulation of MARK2 in lung cell lines revealed its involvement in cell viability and anchorage-independent growth. Analyses of both manipulated cell lines and clinical tumor specimens identified a potential role for MARK2 in cell cycle activation and DNA repair. Associations between MARK2 and the E2F, Myc/Max and NF-κB pathways were identified by luciferase assays and in-depth assessment of the NF-κB pathway suggests a negative association between MARK2 expression and NF-κB due to activation of non-canonical NF-κB signaling. Finally, we show that high MARK2 expression levels correlate with resistance to cisplatin, a standard first line chemotherapy for lung cancer. Collectively, our work supports a role for MARK2 in promoting malignant phenotypes of lung cancer and potentially modulating response to the DNA damaging chemotherapeutic, cisplatin.

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