ABCB5 explained

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 ABCB5 gene.^{[1] [2]} ABCB5 is an ABC transporter and P-glycoprotein family member principally expressed in physiological skin and human malignant melanoma.^{[3] [4] [5]}

Clinical significance

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, colorectal cancer, and malignant pleural mesothelioma. 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] It has been shown that in some highly aggressive tumors, such as mesothelioma and 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 cancer stem cells and tumor bulk population (in a rheostat manner termed "cancer stem cell rheostasis").^{[10] [11]} 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).^[12]

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.^[13]

Further reading

• Milosevic V et al . Wnt/IL-1β/IL-8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5 . Int. J. Cancer . 146 . 1 . 192–207 . January 2020 . 10.1002/ijc.32419 . 31107974 . 2318/1711962 . 160014053 . free .
• Chen KG, Valencia JC, Gillet JP, Hearing VJ, Gottesman MM . Involvement of ABC transporters in melanogenesis and the development of multidrug resistance of melanoma . Pigment Cell & Melanoma Research . 22 . 6 . 740–9 . December 2009 . 19725928 . 2766009 . 10.1111/j.1755-148X.2009.00630.x .
• Corrocher R, Tedesco F, Rabusin P, De Sandre G . Effect of human erythrocyte stromata on complement activation . British Journal of Haematology . 29 . 2 . 235–41 . February 1975 . 33 . 10.1111/j.1365-2141.1975.tb01817.x . 45491647 .
• Frank NY, Frank MH . ABCB5 gene amplification in human leukemia cells . Leukemia Research . 33 . 10 . 1303–5 . October 2009 . 19477512 . 2760090 . 10.1016/j.leukres.2009.04.035 .
• Chen KG, Szakács G, Annereau JP, Rouzaud F, Liang XJ, Valencia JC, Nagineni CN, Hooks JJ, Hearing VJ, Gottesman MM . Principal expression of two mRNA isoforms (ABCB 5alpha and ABCB 5beta) of the ATP-binding cassette transporter gene ABCB 5 in melanoma cells and melanocytes . Pigment Cell Research . 18 . 2 . 102–12 . April 2005 . 15760339 . 10.1111/j.1600-0749.2005.00214.x . 3915408 .
• Huang Y, Anderle P, Bussey KJ, Barbacioru C, Shankavaram U, Dai Z, Reinhold WC, Papp A, Weinstein JN, Sadée W . Membrane transporters and channels: role of the transportome in cancer chemosensitivity and chemoresistance . Cancer Research . 64 . 12 . 4294–301 . June 2004 . 15205344 . 10.1158/0008-5472.CAN-03-3884 . free .
• Malorni W, Lucia MB, Rainaldi G, Cauda R, Cianfriglia M, Donelli G, Ortona L . Intracellular expression of P-170 glycoprotein in peripheral blood mononuclear cell subsets from healthy donors and HIV-infected patients . Haematologica . 83 . 1 . 13–20 . January 1998 . 9542318 .
• Matalon ST, Drucker L, Fishman A, Ornoy A, Lishner M . The Role of heat shock protein 27 in extravillous trophoblast differentiation . Journal of Cellular Biochemistry . 103 . 3 . 719–29 . February 2008 . 17661346 . 10.1002/jcb.21476 . 8249760 .
• Begley GS, Horvath AR, Taylor JC, Higgins CF . Cytoplasmic domains of the transporter associated with antigen processing and P-glycoprotein interact with subunits of the proteasome . Molecular Immunology . 42 . 1 . 137–41 . January 2005 . 15488952 . 10.1016/j.molimm.2004.07.005 .
• Glessner JT, Bradfield JP, Wang K, Takahashi N, Zhang H, Sleiman PM, Mentch FD, Kim CE, Hou C, Thomas KA, Garris ML, Deliard S, Frackelton EC, Otieno FG, Zhao J, Chiavacci RM, Li M, Buxbaum JD, Berkowitz RI, Hakonarson H, Grant SF . A genome-wide study reveals copy number variants exclusive to childhood obesity cases . American Journal of Human Genetics . 87 . 5 . 661–6 . November 2010 . 20950786 . 2978976 . 10.1016/j.ajhg.2010.09.014 .
• Fukunaga-Kalabis M, Martinez G, Nguyen TK, Kim D, Santiago-Walker A, Roesch A, Herlyn M . Tenascin-C promotes melanoma progression by maintaining the ABCB5-positive side population . Oncogene . 29 . 46 . 6115–24 . November 2010 . 20729912 . 2991494 . 10.1038/onc.2010.350 .
• Cheung ST, Cheung PF, Cheng CK, Wong NC, Fan ST . Granulin-epithelin precursor and ATP-dependent binding cassette (ABC)B5 regulate liver cancer cell chemoresistance . Gastroenterology . 140 . 1 . 344–55 . January 2011 . 20682318 . 10.1053/j.gastro.2010.07.049 .
• Yang JY, Ha SA, Yang YS, Kim JW . p-Glycoprotein ABCB5 and YB-1 expression plays a role in increased heterogeneity of breast cancer cells: correlations with cell fusion and doxorubicin resistance . BMC Cancer . 10 . 388 . 2010 . 20649952 . 2913965 . 10.1186/1471-2407-10-388 . free .
• Sharma BK, Manglik V, Elias EG . 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 . September 2010 . 20638684 . 10.1016/j.jss.2010.03.043 .
• Gazzaniga P, Cigna E, Panasiti V, Devirgiliis V, Bottoni U, Vincenzi B, Nicolazzo C, Petracca A, Gradilone A . CD133 and ABCB5 as stem cell markers on sentinel lymph node from melanoma patients . European Journal of Surgical Oncology . 36 . 12 . 1211–4 . December 2010 . 20573479 . 10.1016/j.ejso.2010.05.001 .
• Ma J, Frank MH . Tumor initiation in human malignant melanoma and potential cancer therapies . Anti-Cancer Agents in Medicinal Chemistry . 10 . 2 . 131–6 . February 2010 . 20184545 . 2885608 . 10.2174/187152010790909254 .
• Schatton T, Schütte U, Frank NY, Zhan Q, Hoerning A, Robles SC, Zhou J, Hodi FS, Spagnoli GC, Murphy GF, Frank MH . Modulation of T-cell activation by malignant melanoma initiating cells . Cancer Research . 70 . 2 . 697–708 . January 2010 . 20068175 . 2883769 . 10.1158/0008-5472.CAN-09-1592 .

Notes and References

1. Allikmets R, Gerrard B, Hutchinson A, Dean M . Characterization of the human ABC superfamily: isolation and mapping of 21 new genes using the expressed sequence tags database . Human Molecular Genetics . 5 . 10 . 1649–55 . October 1996 . 8894702 . 10.1093/hmg/5.10.1649 . free .
2. Frank NY, Pendse SS, Lapchak PH, Margaryan A, Shlain D, Doeing C, Sayegh MH, Frank MH . 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 . November 2003 . 12960149 . 10.1074/jbc.M308700200 . free .
3. Chen KG, Szakács G, Annereau JP, Rouzaud F, Liang XJ, Valencia JC, Nagineni CN, Hooks JJ, Hearing VJ, Gottesman MM . Principal expression of two mRNA isoforms (ABCB 5alpha and ABCB 5beta) of the ATP-binding cassette transporter gene ABCB 5 in melanoma cells and melanocytes . Pigment Cell Research . 18 . 2 . 102–12 . April 2005 . 15760339 . 10.1111/j.1600-0749.2005.00214.x . 3915408 .
4. Frank NY, Margaryan A, Huang Y, Schatton T, Waaga-Gasser AM, Gasser M, Sayegh MH, Sadee W, Frank MH . ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma . Cancer Research . 65 . 10 . 4320–33 . May 2005 . 15899824 . 10.1158/0008-5472.CAN-04-3327 . free .
5. Chen KG, Valencia JC, Gillet JP, Hearing VJ, Gottesman MM . Involvement of ABC transporters in melanogenesis and the development of multidrug resistance of melanoma . Pigment Cell & Melanoma Research . 22 . 6 . 740–9 . December 2009 . 19725928 . 2766009 . 10.1111/j.1755-148X.2009.00630.x .
6. Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, Jordan S, Duncan LM, Weishaupt C, Fuhlbrigge RC, Kupper TS, Sayegh MH, Frank MH . Identification of cells initiating human melanomas . Nature . 451 . 7176 . 345–9 . January 2008 . 18202660 . 3660705 . 10.1038/nature06489 . 2008Natur.451..345S .
7. Ma J, Lin JY, Alloo A, Wilson BJ, Schatton T, Zhan Q, Murphy GF, Waaga-Gasser AM, Gasser M, Stephen Hodi F, Frank NY, Frank MH . Isolation of tumorigenic circulating melanoma cells . Biochemical and Biophysical Research Communications . 402 . 4 . 711–7 . November 2010 . 20977885 . 2998991 . 10.1016/j.bbrc.2010.10.091 .
8. Frank NY, Schatton T, Kim S, Zhan Q, Wilson BJ, Ma J, Saab KR, Osherov V, Widlund HR, Gasser M, Waaga-Gasser AM, Kupper TS, Murphy GF, Frank MH . VEGFR-1 expressed by malignant melanoma-initiating cells is required for tumor growth . Cancer Research . 71 . 4 . 1474–85 . February 2011 . 21212411 . 3083845 . 10.1158/0008-5472.CAN-10-1660 .
9. Wilson BJ, Schatton T, Zhan Q, Gasser M, Ma J, Saab KR, Schanche R, Waaga-Gasser AM, Gold JS, Huang Q, Murphy GF, Frank MH, Frank NY . ABCB5 identifies a therapy-refractory tumor cell population in colorectal cancer patients . Cancer Research . 71 . 15 . 5307–16 . August 2011 . 21652540 . 3395026 . 10.1158/0008-5472.CAN-11-0221 .
10. Milosevic, V. et al. Wnt/IL-1β/IL-8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5.Int. J. Cancer, https://doi.org/10.1002/ijc.32419
11. Wilson BJ, Saab KR, Ma J, Schatton T, Pütz P, Zhan Q, Murphy GF, Gasser M, Waaga-Gasser AM, Frank NY, Frank MH . ABCB5 maintains melanoma-initiating cells through a proinflammatory cytokine signaling circuit . Cancer Research . 74 . 15 . 4196–207 . August 2014 . 24934811 . 4119553. 10.1158/0008-5472.CAN-14-0582 .
12. Wilson BJ, Saab KR, Ma J, Schatton T, Pütz P, Zhan Q, Murphy GF, Gasser M, Waaga-Gasser AM, Frank NY, Frank MH . ABCB5 maintains melanoma-initiating cells through a proinflammatory cytokine signaling circuit . Cancer Research . 74 . 15 . 4196–207 . August 2014 . 24934811 . 4119553. 10.1158/0008-5472.CAN-14-0582 .
13. Ksander BR, Kolovou PE, Wilson BJ, Saab KR, Guo Q, Ma J, McGuire SP, Gregory MS, Vincent WJ, Perez VL, Cruz-Guilloty F, Kao WW, Call MK, Tucker BA, Zhan Q, Murphy GF, Lathrop KL, Alt C, Mortensen LJ, Lin CP, Zieske JD, Frank MH, Frank NY . ABCB5 is a limbal stem cell gene required for corneal development and repair . Nature . 511 . 7509 . 353–7 . July 2014 . 25030174 . 4246512. 10.1038/nature13426 . 2014Natur.511..353K .