Paxillin mutations affect focal adhesions and lead to altered mitochondrial dynamics: Relevance to lung cancer

Ichiro Kawada, Rifat Hasina, Frances E. Lennon, Vytautas P. Bindokas, Peter Usatyuk, Yi Hung C. Tan, Soundararajan Krishnaswamy, Qudsia Arif, George Carey, Robyn D. Hseu, Matthew Robinson, Maria Tretiakova, Toni M. Brand, Mari Iida, Mark K. Ferguson, Deric L. Wheeler, Aliya N. Husain, Viswanathan Natarajan, Everett E. Vokes, Patrick A. SingletonRavi Salgia

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

Cytoskeletal and focal adhesion abnormalities are observed in several types of cancer, including lung cancer. We have previously reported that paxillin (PXN) was mutated, amplified, and overexpressed in a significant number of lung cancer patient samples, that PXN protein was upregulated in more advanced stages of lung cancer compared with lower stages, and that the PXN gene was also amplified in some pre-neoplastic lung lesions. Among the mutations investigated, we previously found that PXN variant A127T in lung cancer cells enhanced cell proliferation and focal adhesion formation and colocalized with the anti-apoptotic protein B Cell Lymphoma 2 (BCL-2), which is known to localize to the mitochondria, among other sites. To further explore the effects of activating mutations of PXN on mitochondrial function, we cloned and expressed wild-type PXN and variants containing the most commonly occurring PXN mutations (P46S, P52L, G105D, A127T, P233L, T255I, D399N, E423K, P487L, and K506R) in a GFP-tagged vector using HE K-293 human embryonic kidney cells. Utilizing live-cell imaging to systematically study the effects of wild-type PXN vs. mutants, we created a model that recapitulates the salient features of the measured dynamics and conclude that compared with wild-type, some mutant clones confer enhanced focal adhesion and lamellipodia formation (A127T, P233L, and P487L) and some confer increased association with BCL-2, Dynamin-related Protein-1 (DRP-1), and Mitofusion-2 (MFN-2) proteins (P233L and D399N). Further, PXN mutants, through their interactions with BCL-2 and DRP-1, could regulate cisplatin drug resistance in human lung cancer cells. The data reported herein suggest that mutant PXN variants play a prominent role in mitochondrial dynamics with direct implications on lung cancer progression and hence, deserve further exploration as therapeutic targets.

Original languageEnglish
Pages (from-to)679-691
Number of pages13
JournalCancer Biology and Therapy
Volume14
Issue number7
DOIs
Publication statusPublished - 2013 Jul 1
Externally publishedYes

Keywords

  • Cell motility
  • Fission
  • Fusion
  • Gene mutation
  • Mitochondria
  • Mitochondrial dynamics
  • Paxillin

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Fingerprint Dive into the research topics of 'Paxillin mutations affect focal adhesions and lead to altered mitochondrial dynamics: Relevance to lung cancer'. Together they form a unique fingerprint.

Cite this