title: ATP11B mediates platinum resistance in ovarian cancer.
abstract: Platinum compounds display clinical activity against a wide variety of solid tumors; however, resistance to these agents is a major limitation in cancer therapy. Reduced platinum uptake and increased platinum export are examples of resistance mechanisms that limit the extent of DNA damage. Here, we report the discovery and characterization of the role of ATP11B, a P-type ATPase membrane protein, in cisplatin resistance. We found that ATP11B expression was correlated with higher tumor grade in human ovarian cancer samples and with cisplatin resistance in human ovarian cancer cell lines. ATP11B gene silencing restored the sensitivity of ovarian cancer cell lines to cisplatin in vitro. Combined therapy of cisplatin and ATP11B-targeted siRNA significantly decreased cancer growth in mice bearing ovarian tumors derived from cisplatin-sensitive and -resistant cells. In vitro mechanistic studies on cellular platinum content and cisplatin efflux kinetics indicated that ATP11B enhances the export of cisplatin from cells. The colocalization of ATP11B with fluorescent cisplatin and with vesicular trafficking proteins, such as syntaxin-6 (STX6) and vesicular-associated membrane protein 4 (VAMP4), strongly suggests that ATP11B contributes to secretory vesicular transport of cisplatin from Golgi to plasma membrane. In conclusion, inhibition of ATP11B expression could serve as a therapeutic strategy to overcome cisplatin resistance.
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Myrthala
authors.initials: M
authors.lastname: Moreno-Smith
authors.forename: J B
authors.initials: JB
authors.lastname: Halder
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.forename: Tamas A
authors.initials: TA
authors.lastname: Gonda
authors.forename: Lingegowda S
authors.initials: LS
authors.lastname: Mangala
authors.forename: Rajesha
authors.initials: R
authors.lastname: Rupaimoole
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.forename: Archana S
authors.initials: AS
authors.lastname: Nagaraja
authors.forename: Kshipra M
authors.initials: KM
authors.lastname: Gharpure
authors.forename: Yu
authors.initials: Y
authors.lastname: Kang
authors.forename: Cristian
authors.initials: C
authors.lastname: Rodriguez-Aguayo
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Vivas-Mejia
authors.forename: Behrouz
authors.initials: B
authors.lastname: Zand
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Schmandt
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Robert R
authors.initials: RR
authors.lastname: Langley
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Jennings
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Coffin
authors.forename: Guillermo N
authors.initials: GN
authors.lastname: Armaiz
authors.forename: Justin
authors.initials: J
authors.lastname: Bottsford-Miller
authors.forename: Sang Bae
authors.initials: SB
authors.lastname: Kim
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Halleck
authors.forename: Mary J C
authors.initials: MJ
authors.lastname: Hendrix
authors.forename: William
authors.initials: W
authors.lastname: Bornman
authors.forename: Menashe
authors.initials: M
authors.lastname: Bar-Eli
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.forename: Zahid H
authors.initials: ZH
authors.lastname: Siddik
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005456:Fluorescent Dyes / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D050765:Qa-SNARE Proteins / Q000378:metabolism; D050683:R-SNARE Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D026901:Membrane Transport Proteins; D050765:Qa-SNARE Proteins; D050683:R-SNARE Proteins; D034741:RNA, Small Interfering; C476456:VAMP4 protein, human; C581992:ATP11B protein, human; D000251:Adenosine Triphosphatases; D002945:Cisplatin