FoxO transcription factors promote AKT Ser473 phosphorylation and renal tumor growth in response to pharmacologic inhibition of the PI3K-AKT pathway.
The PI3K-AKT pathway is hyperactivated in many human cancers, and several drugs to inhibit this pathway, including the PI3K/mTOR dual inhibitor NVP-BEZ235, are currently being tested in various preclinical and clinical trials. It has been shown that pharmacologic inhibition of the PI3K-AKT pathway results in feedback activation of other oncogenic signaling pathways, which likely will limit the clinical utilization of these inhibitors in cancer treatment. However, the underlying mechanisms of such feedback regulation remain incompletely understood. The PI3K-AKT pathway is a validated therapeutic target in renal cell carcinoma (RCC). Here, we show that FoxO transcription factors serve to promote AKT phosphorylation at Ser473 in response to NVP-BEZ235 treatment in renal cancer cells. Inactivation of FoxO attenuated NVP-BEZ235-induced AKT Ser473 phosphorylation and rendered renal cancer cells more susceptible to NVP-BEZ235-mediated cell growth suppression in vitro and tumor shrinkage in vivo. Mechanistically, we showed that FoxOs upregulated the expression of Rictor, an essential component of MTOR complex 2, in response to NVP-BEZ235 treatment and revealed that Rictor is a key downstream target of FoxOs in NVP-BEZ235-mediated feedback regulation. Finally, we show that FoxOs similarly modulate the feedback response on AKT Ser473 phosphorylation and renal tumor growth by other phosphoinositide 3-kinase (PI3K) or AKT inhibitor treatment. Together, our study reveals a novel mechanism of PI3K-AKT inhibition-mediated feedback regulation and may identify FoxO as a novel biomarker to stratify patients with RCC for PI3K or AKT inhibitor treatment, or a novel therapeutic target to synergize with PI3K-AKT inhibition in RCC treatment.
Authors' Affiliations: Departments of Experimental Radiation Oncology and Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center; and Program of Cancer Biology, the University of Texas Graduate School of Biomedical Sciences, Houston, Texas.
Aifu
A
Lin
Hai-Long
HL
Piao
Li
L
Zhuang
Dos D
dos D
Sarbassov
Li
L
Ma
Boyi
B
Gan
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C492571:RICTOR protein, human; C531198:dactolisib