Abstract
P-glycoprotein (P-gp) is an ATP-dependent drug pump that confers multidrug resistance (MDR). In addition to its ability to efflux toxins, P-gp can also inhibit apoptosis induced by a wide array of cell death stimuli that rely on activation of intracellular caspases for full function. We therefore hypothesized that P-gp may have additional functions in addition to its role in effluxing xenotoxins that could provide protection to tumor cells against a host response. There have been a number of contradictory reports concerning the role of P-gp in regulating complement activation. Given the disparate results obtained by different laboratories and our published results demonstrating that P-gp does not affect cell death induced by another membranolytic protein, perforin, we decided to assess the role of P-gp in regulating cell lysis induced by a number of different pore-forming proteins. Testing a variety of different P-gp-expressing MDR cell lines produced following exposure of cells to chemotherapeutic agents or by retroviral gene transduction in the complete absence of any drug selection, we found no difference in sensitivity of P-gp(+ve) or P-gp(-ve) cells to the pore-forming proteins complement, perforin, or pneumolysin. Based on these results, we conclude that P-gp does not affect cell lysis induced by pore-forming proteins.
Highlights
P-glycoprotein (P-gp),1 a member of the ATP-binding cassette (ABC) superfamily, is encoded by the MDR1 gene in humans and mdr1a and mdr1b in mice and has been demonstrated to act as a very efficient toxin efflux molecule [1, 2]
Testing a variety of different P-gpexpressing MDR cell lines produced following exposure of cells to chemotherapeutic agents or by retroviral gene transduction in the complete absence of any drug selection, we found no difference in sensitivity of P-gp؉ve or P-gp؊ve cells to the pore-forming proteins complement, perforin, or pneumolysin
In agreement with these studies were those of Bomstein and Fishelson [14], who demonstrated that P-gpϩve tumor cell lines were more sensitive to complement-mediated lysis compared with matched P-gpϪve parental cells
Summary
P-glycoprotein (P-gp), a member of the ATP-binding cassette (ABC) superfamily, is encoded by the MDR1 gene in humans and mdr1a and mdr1b in mice and has been demonstrated to act as a very efficient toxin efflux molecule [1, 2]. Initial studies focused on successfully using anti-P-gp antibodies and rabbit complement to purge autologous bone marrow grafts of residual P-gpϩve MDR cells [12], or complement fixing anti-P-gp antibodies to eliminate P-gpϩve tumors in mouse model systems [13] In agreement with these studies were those of Bomstein and Fishelson [14], who demonstrated that P-gpϩve tumor cell lines were more sensitive to complement-mediated lysis compared with matched P-gpϪve parental cells. In contrast to these findings were two reports demonstrating a role for functional P-gp in inhibiting membrane damage by complement [15, 16] The authors of these studies presented evidence suggesting that P-gp-mediated intracellular alkalinization (pHi) and/or decreased plasma membrane potential (Vmax) resulted in a reduction in the rate of formation of the “membrane attack complex” (MAC) at the cell surface. It was hypothesized that altered pHi and/or Vmax may somehow directly or indirectly affect C9 polymerization, resulting in a net loss of functional MAC formation [16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
