title: Microtubule affinity-regulating kinase 2 is associated with DNA damage response and cisplatin resistance in non-small cell lung cancer.
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.
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada, V5Z, 1L3.
authors.forename: Roland
authors.initials: R
authors.lastname: Hubaux
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada, V5Z, 1L3.
authors.forename: Kelsie L
authors.initials: KL
authors.lastname: Thu
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada, V5Z, 1L3.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Vucic
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada, V5Z, 1L3.
authors.forename: Larissa A
authors.initials: LA
authors.lastname: Pikor
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada, V5Z, 1L3.
authors.forename: Sonia H Y
authors.initials: SH
authors.lastname: Kung
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada, V5Z, 1L3.
authors.forename: Victor D
authors.initials: VD
authors.lastname: Martinez
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada, V5Z, 1L3.
authors.forename: Mitra
authors.initials: M
authors.lastname: Mosslemi
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada, V5Z, 1L3.
authors.forename: Daiana D
authors.initials: DD
authors.lastname: Becker-Santos
authors.affiliation: Hamon Center of Therapeutics, University of Texas South Western, Dallas, TX.
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada, V5Z, 1L3.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lam
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada, V5Z, 1L3.
authors.forename: Wan L
authors.initials: WL
authors.lastname: Lam
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; C094670:MARK2 protein, human; D017346:Protein Serine-Threonine Kinases; D002945:Cisplatin
keywords: DNA damage repair; MARK2; NFκB; cisplatin resistance; lung cancer