The FOXO3-FOXM1 axis: A key cancer drug target and a modulator of cancer drug resistance

Abstract

The FOXO3 and FOXM1 forkhead box transcription factors, functioning downstream of the essential PI3K-Akt, Ras-ERK and JNK/p38MAPK signalling cascades, are crucial for cell proliferation, differentiation, cell survival, senescence, DNA damage repair and cell cycle control. The development of resistance to both conventional and newly emerged molecularly targeted therapies is a major challenge confronting current cancer treatment in the clinic. Intriguingly, the mechanisms of resistance to 'classical' cytotoxic chemotherapeutics and to molecularly targeted therapies are invariably linked to deregulated signalling through the FOXO3 and FOXM1 transcription factors. This is owing to the involvement of FOXO3 and FOXM1 in the regulation of genes linked to crucial drug action-related cellular processes, including stem cell renewal, DNA repair, cell survival, drug efflux, and deregulated mitosis. A better understanding of the mechanisms regulating the FOXO3-FOXM1 axis, as well as their downstream transcriptional targets and functions, may render these proteins reliable and early diagnostic/prognostic factors as well as crucial therapeutic targets for cancer treatment and importantly, for overcoming chemotherapeutic drug resistance.

The transcription factor FOXM1 regulates the balance between proliferation and aberrant differentiation in head and neck squamous cell carcinoma

“…In addition, FOXM1 expression is a major predictor of poor outcome across a large set of cancer types [7]. This strongly supports the concept of FOXM1 as an actionable target for therapy [3,6] and encourages further exploration of FOXM1 function.…”

“…The main gene regulatory activity of FOXM1 is attributed to cell cycle and mitotic control [4,5]. However, recent studies revealed additional activities of FOXM1 as a co-regulator of oncogenic pathways [3,6]. In addition, FOXM1 expression is a major predictor of poor outcome across a large set of cancer types [7].…”

Targeting the FOXM1‐regulated long noncoding RNA TUG1 in osteosarcoma

“…The mutation of P2 significantly decreased the transactivation of the TUG1 promoter by FOXM1. AKT was reported to promote FOXM1 activation by inducing the phosphorylation of FOXO3 for protein degradation . Knockdown of AKT in osteosarcoma cells restrained the expression of TUG1 (Figure G).…”

“…FOXM1 is overexpressed in many different tumors, including osteosarcoma, and contributes to cell proliferation and metastasis . It has been reported that the PI3K/AKT pathway can stimulate the phosphorylation of FOXO3 at Ser294, Ser253, and Thr32 and then eliminate the negative regulation of FOXM1 . We assumed that FOX proteins may influence the expression of TUG1 and showed that FOXM1 could bind to the promoter region of TUG1 by luciferase reporter assays.…”

“…37,38 It has been reported that the PI3K/AKT pathway can stimulate the phosphorylation of FOXO3 at Ser294, Ser253, and Thr32 and then eliminate the negative regulation of FOXM1. 28 We assumed that FOX proteins may influence the expression of TUG1 and showed that FOXM1 could bind to the promoter region of TUG1 by luciferase reporter assays. These data indicated that the expression and activity of TUG1 are controlled by different transcription factors in various tissues.…”