G protein-coupled receptor kinase 5 modifies cancer cell resistance to paclitaxel

Lagman, Joann; Sayegh, Paula; Lee, Christina S.; Sulon, Sarah M.; Jacinto, Alec Z; Sok, Vanessa; Peng, Natalie; Alp, Deniz; Benovic, Jeffrey L.; So, Christopher H.

doi:10.1007/s11010-019-03594-9

Cited by 11 publications

(10 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In cervical and breast cancer cells, Lagman and coworkers demonstrated that GRK5 can phosphorylate HDAC6, increasing the resistance to the antitumor drug, paclitaxel [102]. In patients with renal cell carcinoma, increased levels of GRK5 were associated with poor clinical outcomes [102]. Importantly, as suggested by Zhao and colleagues, this effect was related to the enhanced proliferation of renal cell carcinoma cell lines in the presence of high GRK5 levels [103].…”

Section: Grk5 and Cancermentioning

confidence: 96%

“…Conversely, depletion of GRK5 inhibited in vitro NSCLC cell proliferation and in vivo formation of xenograft tumors [101]. In cervical and breast cancer cells, Lagman and coworkers demonstrated that GRK5 can phosphorylate HDAC6, increasing the resistance to the antitumor drug, paclitaxel [102]. In patients with renal cell carcinoma, increased levels of GRK5 were associated with poor clinical outcomes [102].…”

Section: Grk5 and Cancermentioning

confidence: 99%

See 1 more Smart Citation

Targeting GRK5 for Treating Chronic Degenerative Diseases

Marzano

Rapacciuolo

Ferrara

et al. 2021

IJMS

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors and they are responsible for the transduction of extracellular signals, regulating almost all aspects of mammalian physiology. These receptors are specifically regulated by a family of serine/threonine kinases, called GPCR kinases (GRKs). Given the biological role of GPCRs, it is not surprising that GRKs are also involved in several pathophysiological processes. Particular importance is emerging for GRK5, which is a multifunctional protein, expressed in different cell types, and it has been found located in single or multiple subcellular compartments. For instance, when anchored to the plasma membrane, GRK5 exerts its canonical function, regulating GPCRs. However, under certain conditions (e.g., pro-hypertrophic stimuli), GRK5 translocates to the nucleus of cells where it can interact with non-GPCR-related proteins as well as DNA itself to promote “non-canonical” signaling, including gene transcription. Importantly, due to these actions, several studies have demonstrated that GRK5 has a pivotal role in the pathogenesis of chronic-degenerative disorders. This is true in the cardiac cells, tumor cells, and neurons. For this reason, in this review article, we will inform the readers of the most recent evidence that supports the importance of targeting GRK5 to prevent the development or progression of cancer, cardiovascular, and neurological diseases.

show abstract

Section: Grk5 and Cancermentioning

confidence: 96%

Section: Grk5 and Cancermentioning

confidence: 99%

Targeting GRK5 for Treating Chronic Degenerative Diseases

Marzano

Rapacciuolo

Ferrara

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…GRK5 and HDAC6 form a signaling complex where GRK5 phosphorylates HDAC6 at Ser-21, promoting deacetylase activity, which may contribute to PTX resistance in cancer cells [97]. HeLa cervical cancer cells with reduced GRK5 protein expression show increased PTX sensitivity [98]. Results indicate that reduced GRK5 expression levels lead to decreased phosphorylation of HDAC6 at Ser-21, subsequently lowering HDAC6 activity.…”

Section: Cervical Cancermentioning

confidence: 98%

“…GRK5 forms a signaling complex with, and activates, histone deacetylase 6 (HDAC6) by phosphorylating it at Ser-21. Transient knockdown of GRK5 in MDA-MB-231 cells increased sensitivity to PTX, potentially through blunted HDAC6 activity and higher α-tubulin acetylation [98].…”

Section: Mt Regulators In Mitosis and Cell Cycle Progressionmentioning

confidence: 99%

Mechanisms of Taxane Resistance

Maloney

Hoover

Morejon-Lasso

et al. 2020

Cancers

118

View full text Add to dashboard Cite

The taxane family of chemotherapy drugs has been used to treat a variety of mostly epithelial-derived tumors and remain the first-line treatment for some cancers. Despite the improved survival time and reduction of tumor size observed in some patients, many have no response to the drugs or develop resistance over time. Taxane resistance is multi-faceted and involves multiple pathways in proliferation, apoptosis, metabolism, and the transport of foreign substances. In this review, we dive deeper into hypothesized resistance mechanisms from research during the last decade, with a focus on the cancer types that use taxanes as first-line treatment but frequently develop resistance to them. Furthermore, we will discuss current clinical inhibitors and those yet to be approved that target key pathways or proteins and aim to reverse resistance in combination with taxanes or individually. Lastly, we will highlight taxane response biomarkers, specific genes with monitored expression and correlated with response to taxanes, mentioning those currently being used and those that should be adopted. The future directions of taxanes involve more personalized approaches to treatment by tailoring drug–inhibitor combinations or alternatives depending on levels of resistance biomarkers. We hope that this review will identify gaps in knowledge surrounding taxane resistance that future research or clinical trials can overcome.

show abstract

“…Recent studies provide evidence that phosphorylation of serine 21 of HDAC6 by G protein-coupled receptor kinase 5 (GRK5) promotes deacetylase activity in ovarian (HeLa) and breast (MDA MB 231) cancer cell lines. An increased level of acetylated α-tubulin sensitizes these cells to the anti-apoptotic activity of paclitaxel [257]. The high expression of HDAC6 was also linked to poor prognosis of oral squamous cell carcinoma (OSCC) [258], oncogenic transformation [259], and EMT [260].…”

Section: Microtubule Ptms and Cancermentioning

confidence: 99%

Intrinsic and Extrinsic Factors Affecting Microtubule Dynamics in Normal and Cancer Cells

et al. 2020

View full text Add to dashboard Cite

Microtubules (MTs), highly dynamic structures composed of α- and β-tubulin heterodimers, are involved in cell movement and intracellular traffic and are essential for cell division. Within the cell, MTs are not uniform as they can be composed of different tubulin isotypes that are post-translationally modified and interact with different microtubule-associated proteins (MAPs). These diverse intrinsic factors influence the dynamics of MTs. Extrinsic factors such as microtubule-targeting agents (MTAs) can also affect MT dynamics. MTAs can be divided into two main categories: microtubule-stabilizing agents (MSAs) and microtubule-destabilizing agents (MDAs). Thus, the MT skeleton is an important target for anticancer therapy. This review discusses factors that determine the microtubule dynamics in normal and cancer cells and describes microtubule–MTA interactions, highlighting the importance of tubulin isoform diversity and post-translational modifications in MTA responses and the consequences of such a phenomenon, including drug resistance development.

show abstract

G protein-coupled receptor kinase 5 modifies cancer cell resistance to paclitaxel

Cited by 11 publications

References 80 publications

Targeting GRK5 for Treating Chronic Degenerative Diseases

Targeting GRK5 for Treating Chronic Degenerative Diseases

Mechanisms of Taxane Resistance

Intrinsic and Extrinsic Factors Affecting Microtubule Dynamics in Normal and Cancer Cells

Contact Info

Product

Resources

About