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Disruption of Autophagic Flux and Treatment with the PDPK1 Inhibitor GSK2334470 Synergistically Inhibit Renal Cell

Wei Zhou1, Ji Huang1, Chuansheng Huang2

  • 1Department of Urology, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Clinical Research Center for Cancer, Nanchang, Jiangxi 330000, China.

Journal of Cancer
|February 15, 2024
PubMed

Insights

Targeting 3-Phosphoinositide-dependent kinase 1 (PDPK1) with GSK470 inhibits renal cell carcinoma (RCC) growth by blocking the PI3K-Akt-mTOR pathway. Combining PDPK1 inhibition with autophagy inhibition offers a promising new strategy for RCC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Renal cell carcinoma (RCC) often features activating mutations in the PI3K-Akt-mTOR pathway.
  • 3-Phosphoinositide-dependent kinase 1 (PDPK1) is crucial for PI3K pathway signaling, and mTOR regulates autophagy.
  • The interplay between PDPK1 and autophagy in RCC remains underexplored.

Purpose of the Study:

  • To investigate the anticancer effects of a novel PDPK1 inhibitor, GSK2334470 (GSK470), in RCC.
  • To elucidate the impact of PDPK1 inhibition on the Akt/mTOR pathway and autophagy in RCC.
  • To evaluate the therapeutic potential of combining PDPK1 and autophagy inhibition for RCC.

Main Methods:

  • Utilized GSK470, a specific PDPK1 inhibitor, on two RCC cell lines (A498 and 786-O).
  • Assessed cell proliferation, apoptosis, Western blotting for pathway markers, and autophagy hallmarks (LC3B, electron microscopy, mRFP-EGFP-LC3).
  • Examined *in vivo* efficacy using a mouse xenograft model with GSK470 and chloroquine (autophagy inhibitor).

Main Results:

  • GSK470 significantly inhibited RCC cell proliferation and induced apoptosis.
  • GSK470 downregulated PDPK1 phosphorylation, subsequently inhibiting Akt1 and mTORC1 activity.
  • GSK470 treatment led to increased autophagy markers, and synergistic inhibition of RCC growth was observed when combined with chloroquine *in vitro* and *in vivo*.

Conclusions:

  • PDPK1 inhibition disrupts the PI3K-Akt-mTOR pathway in RCC.
  • Blocking PDPK1 activates a compensatory autophagy response in RCC cells.
  • Combination therapy targeting both PDPK1 and autophagy presents a viable treatment strategy for renal cell carcinoma.
Keywords:
3-Phosphoinositide-dependent kinase 1AutophagyPI3K-Akt-mTOR pathwayRenal cell carcinomaTargeted therapy

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