title: Integrin αβ1, αvβ, α6β effectors p130Cas, Src and talin regulate carcinoma invasion and chemoresistance.
abstract: Ligand engagement by integrins induces receptor clustering and formation of complexes at the integrin cytoplasmic face that controls cell signaling and cytoskeletal dynamics critical for adhesion-dependent processes. This study searches for a subset of integrin effectors that coordinates both tumor cell invasion and resistance to the chemotherapeutic drug cisplatin in oral carcinomas. Candidate integrin effectors were identified in a proteomics screen of proteins recruited to clustered integrin αβ1, α(v)β or α(6)β receptors in oral carcinomas. Proteins with diverse functions including microtubule and actin binding proteins, and factors involved in trafficking, transcription and translation were identified in oral carcinoma integrin complexes. Knockdown of effectors in the oral carcinoma HN12 cells revealed that p130Cas, Dek, Src and talin were required for invasion through Matrigel. Disruption of talin or p130Cas by RNA interference increased resistance to cisplatin, whereas targeting Dek, Src or zyxin reduced HN12 resistance to cisplatin. Analysis of the spreading of HN12 cells on collagen I and laminin I revealed that a decrease in p130Cas or talin expression inhibited spreading on both matrices. Interestingly, a reduction in zyxin expression enhanced spreading on laminin I and inhibited spreading on collagen I. Reduction of Dek, Src, talin or zyxin expression reduced HN12 proliferation by 30%. Proliferation was not affected by a reduction in p130Cas expression. We conclude that p130Cas, Src and talin function in both oral carcinoma invasion and resistance to cisplatin.
authors.affiliation: Department of Oral and Craniofacial Biology, Louisiana State University Health Sciences Center-New Orleans, School of Dentistry, New Orleans, LA 70119, USA.
authors.forename: Hope A
authors.initials: HA
authors.lastname: Sansing
authors.forename: Ali
authors.initials: A
authors.lastname: Sarkeshik
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Vyomesh
authors.initials: V
authors.lastname: Patel
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Yamada
authors.forename: Allison L
authors.initials: AL
authors.lastname: Berrier
mesh_terms: D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D050719:Crk-Associated Substrate Protein / Q000235:genetics / Q000378:metabolism*; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D006801:Humans; D039222:Integrin alpha1beta1 / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000378:metabolism; D039121:Integrin alpha6beta1 / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D011509:Proteoglycans / Q000378:metabolism; D040901:Proteomics; D034741:RNA, Small Interfering / Q000235:genetics; D016608:Talin / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D024042:Collagen Type I; D050719:Crk-Associated Substrate Protein; D004338:Drug Combinations; D039222:Integrin alpha1beta1; D039081:Integrin alpha5beta1; D039121:Integrin alpha6beta1; D007797:Laminin; D011509:Proteoglycans; D034741:RNA, Small Interfering; D016608:Talin; C121346:laminin 1; C059485:matrigel; D003094:Collagen; D019061:src-Family Kinases; D002945:Cisplatin