β-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer

Tenbaum SP, Ordonez-Moran P, Puig I, Chicote I, Arques O, Landolfi S, Fernandez Y, Herance JR, Gispert JD, Mendizabal L, Aguilar S, Ramon y Cajal S, Schwartz S, Jr., Vivancos A, Espin E, Rojas S, Baselga J, Tabernero J, Munoz A, Palmer HG.

(2012). Nat. Med. 18: 892-901.

Speaker: Shu-Ching Lin (林紓晴)                 Time: 14:00~15:00, Sep. 26, 2012

Commentator: Dr. Pai-Sheng Chen (陳百昇老師)               Place: Room 601

Abstract:

The Wnt-β-catenin pathway is abnormally activated in more than 90% of colon cancer patients. V-akt murine thymoma viral oncogene homolog (AKT) is frequently activated by activation mutations in colon and many other cancers. Forkhead box O3 (FOXO3a) transcription factors are primarily regulated by the phosphoinositide-3-kinase (PI3k)–Akt pathway via phosphorylation and nuclear exclusion¹. FOXO3a is a tumor suppressor, which induces cell-cycle arrest and apoptosis. Previous studies indicated that FOXO3a is one of those transcription factors for which β-cateninacts as a transcriptional co-activator. In this study, the authors found that the enhanced of FOXO3a and β-catenin colocalizes in nuclear and promotes cell scattering and metastasis, but inhibits cell apoptosis. This result indicates that β-catenin divertes FOXO3a-induced apoptosis to metastasis. The anti-tumor drug API-2, inhibitor of AKT, relocated FOXO3a back to the nuclear. This effect promoted metastasis when β-catenin was high expressed in nuclear. In primary cultures and in corresponding xenograft tumors in mice, the authors also found the accumulated β-catenin in nuclearconfered resistance FOXO3a-induced apoptosis regulated by PI3K and AKT inhibitors. This resistance is reversed by XAV-939, an inhibitor of Wnt–β-catenin signaling. In conclusion, the high amount of β-catenin accumulates in nuclear leads to activation of FOXO3a as metastasis inductor rather than apoptotic tumor suppressor. To provide a safer personalized treatment, this study reveals that we can evaluate the β-catenin status of patients before they receive treatment to avoid promotion of metastasis caused by FOXO3a and β-catenin.

References:

1. Reagan-Shaw S, Ahmad N. (2007). The role of Forkhead-box Class O (FoxO) transcription factors in cancer: a target for the management of cancer. Toxicology and applied pharmacology 224: 360-368.

2. Essers MA, de Vries-Smits LM, Barker N, Polderman PE, Burgering BM, Korswagen HC. (2005). Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 308: 1181-1184.