RKIP and YY1: The ‘good’ and the ‘bad’ shields in the protection of cancer spreading and resistance to therapies
Cancer originates from all of the uncorrected mutations occurring in the DNA of the cell that lead to abnormal cell growth. Accordingly, the accumulation of these mutations transforms a normal cell into an “immortal” cancer cell with aggressive and invasive behavior among the rest of the normal cells; a process known as tumor spreading, or metastasis. Furthermore, cancer cells require additional modifications to support their survival and avoid their eradication mediated by the immune system, or conventional treatment modalities.
To understand the above cancer cell behavior, we present the interrelationship between two cellular proteins that we have studied, namely, RKIP (Raf Kinase Inhibitor Protein) and YY1 (Yin Yang 1). We have found that RKIP and YY1 have opposing roles in the regulation of tumor cell growth, metastasis, and resistance to therapies. As predicted, RKIP is poorly expressed in many cancer types, since it augments tumor response to therapy and inhibits cancer metastasis. In contrast, the YY1 protein that enhances tumor growth, metastasis, and resistance to therapies is overexpressed in the majority of cancers. Given the inverse correlation found between the expression levels of YY1 and RKIP in many solid and hematological malignancies, we have hypothesized and determined that these two proteins are closely related and that each regulates negatively the expression of the other, through several complex and interconnected signaling pathways (roads). Similar to traffic lights, YY1 (the green light) and RKIP (the red light), promote or inhibit tumor properties, respectively (Fig. 1). On this context, we describe and analyze five possible interconnected signaling roads, which explain the inverse relationship found between the expression levels of RKIP and YY1 in cancers. Each interconnected road is comprised by multiple interactions among intermediate proteins with established pro- or anti-cancer functions. These five interconnecting roads may behave each individually, or together, and overall influencing the ultimate expression levels of YY1 and RKIP; hence leading to determining new approaches to predict tumor cell response to chemo-/immuno-therapies, as well as tumor aggressiveness.
In addition, these pathways also provide novel prognostic motifs and therapeutic targets and establish the significance of developing new regimens that will be able either to increase or diminish RKIP and YY1 expression levels, respectively. This will result in blocking the cancer cell survival, growth and spreading, as well as overcoming tumor resistance to existing anti-tumor therapies. Noteworthy, alternative combinational therapeutic approaches, that involve the above suggested regimens and low doses of the conventional therapies may augment the efficacy of the anti-cancer treatments and the overall patients’ survival.
Benjamin Bonavida 1, Stavroula Baritaki 2
1Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
2Division of Surgical Oncology, School of Medicine, University of Crete, Heraklion, Crete, Greece
Inverse correlation between the metastasis suppressor RKIP and the metastasis inducer YY1: Contrasting roles in the regulation of chemo/immuno-resistance in cancer.
Wottrich S, Kaufhold S, Chrysos E, Zoras O, Baritaki S, Bonavida B
Drug Resist Updat. 2017 Jan
|A formula for better asthma, cold and heart medications Imagine that you had found a way to drop the dose of your asthma medication ten-fold, increase its duration of activity from a couple of hours to all day, and…|
|MTA3: A master coregulator of physiology and oncogenesis The discovery of novel therapeutics for treatment of cancer is today’s prime concern due to abundantly increasing cancer drug resistance and deaths worldwide. MTA3, a member of metastasis-associated protein (MTA)…|
|Cyagen Biosciences – Helping you choose the right… While many animal models are available “ off the shelf ” through various repositories and collaborations, generation of novel animal models has allowed for more effective studies, not limited by…|
|Young adults with autism show improved social… Researchers at the Semel Institute for Neuroscience and Human Behavior at UCLA have found that a social skills program for high - functioning young adults with autism spectrum disorder significantly…|
|The oncolytic virus ∆PK has multi-modal anti-tumor activity Oncolytic viruses (OVs) are an emerging cancer therapeutic based on tumor cell lysis by replicating virus and the resulting release of cellular proteins [viz. tumor-associated antigens (TAAs)], which modulate tumor…|
|Using nanotechnology to outsmart pancreatic cancer Cancer is a versatile disease and makes use of complex cellular signaling networks to defend itself against a host of treatments. Pancreatic cancer in particular has proven challenging with tenacious…|