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

Matthew Moghaddam; Silvia Vivarelli; Luca Falzone; Massimo Libra; Benjamin Bonavida

doi:10.37349/etat.2023.00128

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

Explor Target Antitumor Ther. 2023;4(2):170-207. doi: 10.37349/etat.2023.00128. Epub 2023 Apr 20.

Authors

Matthew Moghaddam¹, Silvia Vivarelli², Luca Falzone³, Massimo Libra^{4

5}, Benjamin Bonavida¹

Affiliations

¹ Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA), East Los Angeles, CA 90095, USA.
² Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Occupational Medicine Section, University of Messina, 98125 Messina, Italy.
³ Epidemiology and Biostatistics Unit, National Cancer Institute IRCCS Fondazione G. Pascale, 80131 Naples, Italy.
⁴ Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy.
⁵ Research Centre for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy.

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.

Keywords: PTEN; RKIP; bioinformatics; cross-talks; resistance; signaling.

Publication types

Review