The cyclic GMP/protein kinase G pathway as a therapeutic target in head and neck squamous cell carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) is an aggressive disease with high mortality. Treatments, which can result in significant morbidity, have not substantially changed in three decades. The second messenger cyclic GMP (cGMP), which targets protein kinase G (PKG), is generated by guanylate cyclases (GCs), and is rapidly hydrolyzed by phosphodiesterases (PDEs). Activation of the cGMP/PKG pathway is antineoplastic in several cancer types, but its impact on HNSCC has not been fully exploited. We found differential expression of critical components of this pathway in four HNSCC cell lines. Several activators of soluble GC (sGC), as well as inhibitors of PDE5, increased intracellular cGMP, reduced cell viability, and induced apoptosis in HNSCC cells. The apoptotic effects of the sGC activator BAY 41-2272 and the PDE5 inhibitor Tadalafil (Cialis) were mediated by PKG. Furthermore, Tadalafil substantially reduced the growth of CAL27-derived tumors in athymic mice. Several drugs which either activate sGC or inhibit PDE5 are approved for treatment of nonmalignant conditions. These drugs could be repurposed as novel and effective therapeutics in patients with head and neck cancer.

Quantitative Analysis of Proteome in Non-functional Pituitary Adenomas: Clinical Relevance and Potential Benefits for the Patients

“…It has been reported that cGMP promoted tumorigenesis and anticancer effects. For example, the activated cGMP/PKG pathway induced multiple cancers (33,(35)(36)(37). Studies found specifically activated protein kinase G1 (PKG1) triggered MAPK signaling pathway to promote growth of melanoma (38).…”

Soluble guanylate cyclase stimulators increase sensitivity to cisplatin in head and neck squamous cell carcinoma cells

“…We have previously shown that BAY reduced the viability of HNSCC cells primarily by inducing apoptosis, while only slightly reducing cell proliferation [22]. Here we examined whether YC-1 or BAY enhanced the apoptotic effects of cisplatin in HNSCC cells.…”

“…Thus, PKG-Iα has been reported to have pro-tumorigenic effects [35, 36], while PKG-Iβ [37, 38] and PKG-II [13] had antineoplastic effects. Our previous studies have shown that all four HNSCC cell lines examined express PKGIβ and PKGII, but had no detectable levels of PKGIα transcripts [22]. …”

“…For example, Riociguat, a NO-independent sGC stimulator, is used to treat pulmonary hypertension [19], while selective PDE5 inhibitors such as Tadalafil (Cialis) and Sildenafil (Viagra) are used to treat erectile dysfunction [20]. Thomson et al [21] were the first to link the cGMP/PKG pathway to inhibition of growth of colon cancer cells by a mechanism involving the suppression of β-catenin.We recently reported that activation of the cGMP pathway in HNSCC cells by sGC activators or PDE5 inhibitors reduced cell viability and clonogenic growth and induced apoptosis [22]. Others found that YC-1, a sGC activator, as well as PDE5 inhibitors, enhance the efficacy of a variety of chemotherapeutic agents [23-25].…”

Hydroalcoholic Extract of Levisticum officinale Increases cGMP Signaling Pathway by Down-Regulating PDE5 Expression and Induction of Apoptosis in MCF-7 and MDA-MB-468 Breast Cancer Cell Lines

“…cGMP can activate cGMP-dependent protein kinase (PKG) and PDE enzymes. It also causes ion fluxes and protein phosphorylation that can affect genes expression or other cellular responses [6,11,12] . Recently, the overexpression of PDE5 has been reported in several human carcinomas, including breast cancer, and suggested that PDE5 expression has positive correlation with tumor grade, lymph node involvement, and invasive potential, as well as decreasing survival rate in patients.…”