title: Identification of an AAA ATPase VPS4B-dependent pathway that modulates epidermal growth factor receptor abundance and signaling during hypoxia.
abstract: VPS4B, an AAA ATPase (ATPase associated with various cellular activities), participates in vesicular trafficking and autophagosome maturation in mammalian cells. In solid tumors, hypoxia is a common feature and an indicator of poor treatment outcome. Our studies demonstrate that exogenous or endogenous (assessed with anchorage-independent three-dimensional multicellular spheroid culture) hypoxia induces VPS4B downregulation by the ubiquitin-proteasome system. Inhibition of VPS4B function by short hairpin VPS4B (sh-VPS4B) or expression of dominant negative VPS4B(E235Q) promotes anchorage-independent breast cancer cell growth and resistance to gefitinib, U0126, and genotoxicity. Biochemically, hyperactivation of epidermal growth factor receptor (EGFR), a receptor tyrosine kinase essential for cell proliferation and survival, accompanied by increased EGFR accumulation and altered intracellular compartmentalization, is observed in cells with compromised VPS4B. Furthermore, enhanced FOS/JUN induction and AP-1 promoter activation are noted in EGF-treated cells with VPS4B knockdown. However, VPS4B depletion does not affect EGFRvIII stability or its associated signaling. An inverse correlation between VPS4B expression and EGFR abundance is observed in breast tumors, and high-grade or recurrent breast carcinomas exhibit lower VPS4B expression. Together, our findings highlight a potentially critical role of VPS4B downregulation or chronic-hypoxia-induced VPS4B degradation in promoting tumor progression, unveiling a nongenomic mechanism for EGFR overproduction in human breast cancer.
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, California, USA.
authors.forename: H Helen
authors.initials: HH
authors.lastname: Lin
authors.forename: Xu
authors.initials: X
authors.lastname: Li
authors.forename: Jo-Lin
authors.initials: JL
authors.lastname: Chen
authors.forename: Xiuzhu
authors.initials: X
authors.lastname: Sun
authors.forename: Fariba Norouziyan
authors.initials: FN
authors.lastname: Cooper
authors.forename: Yun-Ru
authors.initials: YR
authors.lastname: Chen
authors.forename: Wenyu
authors.initials: W
authors.lastname: Zhang
authors.forename: Yiyin
authors.initials: Y
authors.lastname: Chung
authors.forename: Angela
authors.initials: A
authors.lastname: Li
authors.forename: Chun-Ting
authors.initials: CT
authors.lastname: Cheng
authors.forename: Lixin
authors.initials: L
authors.lastname: Yang
authors.forename: Xutao
authors.initials: X
authors.lastname: Deng
authors.forename: Xiyong
authors.initials: X
authors.lastname: Liu
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Johnson
authors.forename: Hsiu-Ming
authors.initials: HM
authors.lastname: Shih
authors.forename: Austin
authors.initials: A
authors.lastname: Yang
authors.forename: David K
authors.initials: DK
authors.lastname: Ann
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D018874:Spheroids, Cellular
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D012333:RNA, Messenger; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; C490304:VPS4B protein, human