Cancer resistance via the downregulation of the tumor suppressors RKIP and PTEN expressions: therapeutic implications

Abstract

The Raf kinase inhibitor protein (RKIP) has been reported to be underexpressed in many cancers and plays a role in the regulation of tumor cells’ survival, proliferation, invasion, and metastasis, hence, a tumor suppressor. RKIP also regulates tumor cell resistance to cytotoxic drugs/cells. Likewise, the tumor suppressor, phosphatase and tensin homolog (PTEN), which inhibits the phosphatidylinositol 3 kinase (PI3K)/AKT pathway, is either mutated, underexpressed, or deleted in many cancers and shares with RKIP its anti-tumor properties and its regulation in resistance. The transcriptional and posttranscriptional regulations of RKIP and PTEN expressions and their roles in resistance were reviewed. The underlying mechanism of the interrelationship between the signaling expressions of RKIP and PTEN in cancer is not clear. Several pathways are regulated by RKIP and PTEN and the transcriptional and post-transcriptional regulations of RKIP and PTEN is significantly altered in cancers. In addition, RKIP and PTEN play a key role in the regulation of tumor cells response to chemotherapy and immunotherapy. In addition, molecular and bioinformatic data revealed crosstalk signaling networks that regulate the expressions of both RKIP and PTEN. These crosstalks involved the mitogen-activated protein kinase (MAPK)/PI3K pathways and the dysregulated nuclear factor-kappaB (NF-κB)/Snail/Yin Yang 1 (YY1)/RKIP/PTEN loop in many cancers. Furthermore, further bioinformatic analyses were performed to investigate the correlations (positive or negative) and the prognostic significance of the expressions of RKIP or PTEN in 31 different human cancers. These analyses were not uniform and only revealed that there was a positive correlation between the expression of RKIP and PTEN only in few cancers. These findings demonstrated the existence of signaling cross-talks between RKIP and PTEN and both regulate resistance. Targeting either RKIP or PTEN (alone or in combination with other therapies) may be sufficient to therapeutically inhibit tumor growth and reverse the tumor resistance to cytotoxic therapies.

SIRT4 as a novel interactor and candidate suppressor of C-RAF kinase in MAPK signaling

“…Moreover, RKTG (RAF kinase trapping to Golgi) has been suggested to regulate the spatial localization of C-RAF by trapping it to the Golgi, thereby altering the interaction of C-RAF with RAS and MEK1 and inhibiting ERK signaling ( Feng et al, 2007 ). Another regulator of C-RAF is RKIP ( Yesilkanal & Rosner, 2018 ; Touboul et al, 2021 ; Cessna et al, 2022 ; Moghaddam et al, 2023 ), which binds to the N-terminal region of C-RAF, thereby inhibiting C-RAF–mediated phosphorylation and activation of MEK1/2 ( Park et al, 2006 ; Rath et al, 2008 ). Interestingly, a comparison between RKIP and SIRT4 reveals cellular and functional similarities: (i) both proteins are tumor suppressors ( Jeong et al, 2013 ; Moghaddam et al, 2023 ) that inhibit/prevent C-RAF activation, and their expression is usually down-regulated in cancer ( Yesilkanal & Rosner, 2018 ; Bai et al, 2020 ; Tomaselli et al, 2020 ; Wang et al, 2020 ), although the underlying mechanisms for SIRT4 are still unclear; (ii) SIRT4 and RKIP are both involved in the regulation of mitotic cell division.…”

“…Another regulator of C-RAF is RKIP ( Yesilkanal & Rosner, 2018 ; Touboul et al, 2021 ; Cessna et al, 2022 ; Moghaddam et al, 2023 ), which binds to the N-terminal region of C-RAF, thereby inhibiting C-RAF–mediated phosphorylation and activation of MEK1/2 ( Park et al, 2006 ; Rath et al, 2008 ). Interestingly, a comparison between RKIP and SIRT4 reveals cellular and functional similarities: (i) both proteins are tumor suppressors ( Jeong et al, 2013 ; Moghaddam et al, 2023 ) that inhibit/prevent C-RAF activation, and their expression is usually down-regulated in cancer ( Yesilkanal & Rosner, 2018 ; Bai et al, 2020 ; Tomaselli et al, 2020 ; Wang et al, 2020 ), although the underlying mechanisms for SIRT4 are still unclear; (ii) SIRT4 and RKIP are both involved in the regulation of mitotic cell division. SIRT4 achieves this through centrosomal localization and potential control of microtubule dynamics ( Bergmann et al, 2020 ), whereas RKIP achieves this through interaction with Aurora-B and control of the mitotic checkpoint ( Eves et al, 2006 ); and finally, (iii) both SIRT4 ( Lang et al, 2017 ; Li et al, 2023 ) and RKIP are linked to the regulation of autophagy.…”

“…Addressing the molecular control of C-RAF by interacting regulators and the underlying molecular and structural mechanisms is still necessary for understanding the complex landscape of MAPK network signaling. Several proteins that bind and regulate C-RAF have been identified, including RKIP (RAF1 kinase inhibitor protein), which functions as an anti-metastatic tumor suppressor and is down-regulated in various cancers ( Yesilkanal & Rosner, 2018 ; Touboul et al, 2021 ; Cessna et al, 2022 ; Moghaddam et al, 2023 ). RKIP binds to the N-terminal region of C-RAF and therefore inhibits C-RAF–mediated phosphorylation and activation of MEK1/2 ( Rath et al, 2008 ).…”