ATP-binding cassette sub-family B member 5 also known as P-glycoprotein ABCB5 is a plasma membrane-spanning protein that in humans is encoded by the ABCB5gene.[1][2] ABCB5 is an ABC transporter and P-glycoprotein family member principally expressed in physiological skin and human malignant melanoma.[3][4][5]
ABCB5 has been suggested to regulate skin progenitor cell fusion and mediate chemotherapeutic drug resistance in stem-like tumor cell subpopulations in human malignant melanoma. It is commonly over-expressed on circulating melanoma tumour cells.[6][7] Furthermore, the ABCB5+ melanoma- initiating cells were demonstrated to express FLT1 (VEGFR1) receptor tyrosine kinase which was functionally required for efficient xenograft tumor formation, as demonstrated by shRNA knockdown experiments.[8]
In colorectal cancer, ABCB5 was shown to act as a mediator of 5-FU patient chemoresistance, and had a further direct role in tumorigenesis shown by shRNA-mediated colorectal cancer cell-line ABCB5 knockdowns that impeded tumorigenesis in human-to-mouse xenografts.[9] In melanoma, ABCB5 contributes to multi-drug chemotherapy resistance, and tumor growth, controlling a proinflammatory signaling circuit utilizing TLR4, IL-1β, IL8 and CXCR1 signaling involving reciprocal paracrine interactions between the melanoma stem cell and tumor bulk population (in a rheostat manner termed "cancer stem cell rheostasis"). ABCB5 was shown to maintain the slow-cycling melanoma stem cells using this cytokine signaling loop, which became more differentiated upon ABCB5 interference (e.g. WFDC1 melanocyte differentiation marker increased, cancer cells were faster growing in vitro, tumors were more pigmented), or CXCR1 blockade (slow-cycling ABCB5+ cells entered the cell-cycle).[10]
In normal physiology ABCB5 is a functional marker for adult limbal stem cells of the cornea. ABCB5+ cells could regrow a human cornea on a mouse with limbal stem cell deficiency (LSCD - a blindness disease of the corneal limbus) while ABCB5- cells could not, indicating a therapeutic potential for treating some types of blindness. ABCB5 was further shown to be anti-apoptotic in these adult stem cells.[11]
References
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↑Frank NY, Pendse SS, Lapchak PH, Margaryan A, Shlain D, Doeing C, Sayegh MH, Frank MH (November 2003). "Regulation of progenitor cell fusion by ABCB5 P-glycoprotein, a novel human ATP-binding cassette transporter". The Journal of Biological Chemistry. 278 (47): 47156–65. doi:10.1074/jbc.M308700200. PMID12960149.
↑Frank NY, Margaryan A, Huang Y, Schatton T, Waaga-Gasser AM, Gasser M, Sayegh MH, Sadee W, Frank MH (May 2005). "ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma". Cancer Research. 65 (10): 4320–33. doi:10.1158/0008-5472.CAN-04-3327. PMID15899824.
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Malorni W, Lucia MB, Rainaldi G, Cauda R, Cianfriglia M, Donelli G, Ortona L (January 1998). "Intracellular expression of P-170 glycoprotein in peripheral blood mononuclear cell subsets from healthy donors and HIV-infected patients". Haematologica. 83 (1): 13–20. PMID9542318.
Matalon ST, Drucker L, Fishman A, Ornoy A, Lishner M (February 2008). "The Role of heat shock protein 27 in extravillous trophoblast differentiation". Journal of Cellular Biochemistry. 103 (3): 719–29. doi:10.1002/jcb.21476. PMID17661346.
Begley GS, Horvath AR, Taylor JC, Higgins CF (January 2005). "Cytoplasmic domains of the transporter associated with antigen processing and P-glycoprotein interact with subunits of the proteasome". Molecular Immunology. 42 (1): 137–41. doi:10.1016/j.molimm.2004.07.005. PMID15488952.
Sharma BK, Manglik V, Elias EG (September 2010). "Immuno-expression of human melanoma stem cell markers in tissues at different stages of the disease". The Journal of Surgical Research. 163 (1): e11–5. doi:10.1016/j.jss.2010.03.043. PMID20638684.
Gazzaniga P, Cigna E, Panasiti V, Devirgiliis V, Bottoni U, Vincenzi B, Nicolazzo C, Petracca A, Gradilone A (December 2010). "CD133 and ABCB5 as stem cell markers on sentinel lymph node from melanoma patients". European Journal of Surgical Oncology. 36 (12): 1211–4. doi:10.1016/j.ejso.2010.05.001. PMID20573479.