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Rack1 mediates Src binding to drug transporter P-glycoprotein and modulates its activity through regulating

Yanling Fan1,2,3,4, Weiyao Si1,2,3,4, Wei Ji1,2,3,4

  • 1Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China.

Cell Death & Disease
|May 23, 2019
PubMed

Insights

Rack1 and Src regulate P-glycoprotein (P-gp) transport activity, conferring drug resistance in breast cancer without changing P-gp levels. This discovery offers new targets for overcoming multidrug resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Multidrug resistance (MDR) in breast cancer hinders chemotherapy effectiveness.
  • P-glycoprotein (P-gp) effluxes anticancer drugs, contributing significantly to MDR.
  • Mechanisms regulating P-gp transport activity, distinct from expression levels, are poorly understood.

Purpose of the Study:

  • To investigate the regulatory mechanisms of P-gp transport activity in drug-resistant breast cancer cells.
  • To identify novel signaling pathways involved in modulating P-gp function.
  • To explore Rack1 and Src as potential targets for reversing drug resistance.

Main Methods:

  • Investigated the roles of Rack1 and Src in modulating P-gp transport activity.
  • Examined the interaction between Rack1, Src, and caveolin-1 (Cav1).
  • Assessed the effect of Rack1 and Src on Cav1 phosphorylation and its subsequent impact on P-gp activity.

Main Results:

  • Rack1 and Src modulate P-gp transport activity, conferring drug resistance without altering P-gp protein levels.
  • Rack1 and Src regulate P-gp activity via modulation of caveolin-1 (Cav1) phosphorylation.
  • Rack1 acts as a signaling hub, facilitating Src binding to P-gp and promoting Cav1 phosphorylation, thereby overcoming Cav1's inhibitory effect on P-gp.

Conclusions:

  • Rack1 and Src play critical roles in modulating P-gp activity in drug-resistant cells.
  • These findings elucidate novel mechanisms regulating P-gp transport.
  • Rack1 presents a potential therapeutic target for reversing multidrug resistance in breast cancer.

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