title: Mutant p53-R273H mediates cancer cell survival and anoikis resistance through AKT-dependent suppression of BCL2-modifying factor (BMF).
abstract: p53 is the most frequently mutated tumor-suppressor gene in human cancers. Unlike other tumor-suppressor genes, p53 mutations mainly occur as missense mutations within the DNA-binding domain, leading to the expression of full-length mutant p53 protein. Mutant p53 proteins not only lose their tumor-suppressor function, but may also gain new oncogenic functions and promote tumorigenesis. Here, we showed that silencing of endogenous p53-R273H contact mutant, but not p53-R175H conformational mutant, reduced AKT phosphorylation, induced BCL2-modifying factor (BMF) expression, sensitized BIM dissociation from BCL-XL and induced mitochondria-dependent apoptosis in cancer cells. Importantly, cancer cells harboring endogenous p53-R273H mutant were also found to be inherently resistant to anoikis and lack BMF induction following culture in suspension. Underlying these activities is the ability of p53-R273H mutant to suppress BMF expression that is dependent on constitutively active PI3K/AKT signaling. Collectively, these findings suggest that p53-R273H can specifically drive AKT signaling and suppress BMF expression, resulting in enhanced cell survivability and anoikis resistance. These findings open the possibility that blocking of PI3K/AKT will have therapeutic benefit in mutant p53-R273H expressing cancers.
authors.affiliation: 1] School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia [2] Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: B S
authors.initials: BS
authors.lastname: Tan
authors.affiliation: 1] School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia [2] Oral Cancer Research and Co-ordinating Center (OCRCC), Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia [3] Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia.
authors.forename: K H
authors.initials: KH
authors.lastname: Tiong
authors.affiliation: 1] School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia [2] Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: H L
authors.initials: HL
authors.lastname: Choo
authors.affiliation: Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: F Fei-Lei
authors.initials: FF
authors.lastname: Chung
authors.affiliation: 1] School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia [2] Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: L-W
authors.initials: LW
authors.lastname: Hii
authors.affiliation: 1] School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia [2] Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: S H
authors.initials: SH
authors.lastname: Tan
authors.affiliation: School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: I K S
authors.initials: IK
authors.lastname: Yap
authors.affiliation: ANU Medical School, Canberra Hospital Campus, The Canberra Hospital Building 4, Garran, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Pani
authors.affiliation: School of Medicine, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
authors.forename: N T W
authors.initials: NT
authors.lastname: Khor
authors.affiliation: School of Medicine, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: S F
authors.initials: SF
authors.lastname: Wong
authors.affiliation: UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
authors.forename: R
authors.initials: R
authors.lastname: Rosli
authors.affiliation: Faculty of Medicine and Health Sciences, University Tunku Abdul Rahman, Bandar Sungai Long, Selangor, Malaysia.
authors.forename: S-K
authors.initials: SK
authors.lastname: Cheong
authors.affiliation: 1] School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia [2] Center for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia [3] School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: C-O
authors.initials: CO
authors.lastname: Leong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D023102:Anoikis / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C486655:BMF protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt