CD44 inhibition attenuates EGFR signaling and enhances cisplatin sensitivity in human EGFR wild‑type non‑small‑cell lung cancer cells

Abstract

cluster of differentiation 44 (cd44) as a transmembrane glycoprotein is found to be expressed in non-small cell lung cancer (NSCLC), is significantly associated with NSLC progression, metastasis and drug resistance. This study aimed to explore whether CD44 inhibition improves the sensitivity of epidermal growth factor receptor (EGFR) wild-type NSCLC cells to cisplatin and how it affects wild-type EGFR in NSCLC cells. Small interfering RNA was used to knockdown CD44 expression in EGFR wild-type NSCLC cell line H460. Results suggested that CD44 downregulation reduced cell growth, promoted G 0 /G 1 cell cycle arrest and induced cell apoptosis in H460 cells and these effects were evidently enhanced when in combination with cisplatin. Deactivation of EGFR signaling pathway including EGFR phosphorylation and its downstream molecules, targets ERK, AKT1 and SRC which were also observed in CD44-silenced H460 cells with or without EGF stimulation. Furthermore, the CD44 expression level was positively correlated with wild-type EGFR level in human lung adenocarcinoma tissues and CD44 inhibition significantly accelerated the degradation of EGFR, indicating that enhanced sensitivity of H460 cells to cisplatin by downregulation of CD44 might be due to EGFR degradation. This study demonstrated that suppression of CD44 deactivated EGFR signals in NSCLC cells with wild-type EGFR, thereby contributing to the inhibition of cell proliferation and the reinforcement of cisplatin sensitivity. It is suggested that downregulation of CD44 could be a novel potential therapeutic strategy for the treatment of EGFR wild-type NScLc.

Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung Cancer

“…CD44 (also known as CSPG8) is another major CSPG identified in our analysis that is involved in tumorigenesis. CD44 inhibition attenuates EGFR signaling and enhances cisplatin sensitivity in EGFR wild-type NSCLC [42]. Additionally, CD44 promotes PD-L1 expression and its tumor-intrinsic function in both breast and lung malignancies [43].…”

Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer

“…CD44 has also been established as a potential CSC marker that contributes to cancer proliferation, metastasis, and drug resistance [ 314 ]. The expression of CD44 has been correlated with the EGFR level in a variety of cancer, and their expression is positively regulated reciprocally [ 315 ]. CD44 also serves as a co-receptor for RTKs to stimulate downstream signaling pathways [ 309 ].…”

The impact of molecular tumor profiling on the design strategies for targeting myeloid leukemia and EGFR/CD44-positive solid tumors

“…Cluster of differentiation 44 (CD44) promotes carcinogenesis and progression. It also acts as a co-receptor in the EGFR signaling cascade [ 2 , 68 ]. The expression level of CD44 is positively correlated with the wild-type EGFR level in cancer tissues.…”

“…Literature data points to combinatorial therapy, coadministration, and codelivery of agents by nanomedicines as a successful approach to bypass signaling inhibition, combat anticancer drug resistance, and increase the efficacy of the clinical treatment. Further advances in molecular screening and novel discoveries related to unique cancer molecular signatures, including the specific biomarkers of the cancer stem cells and the correlated action of receptors in cancer survival, such as the frequently reported CD44/EGFR axis, resulted in useful strategies for the development of dual-targeted NDDSs capable of attacking multiple targets for a more efficacious cancer treatment [ 2 ]. With this in mind, in this article we will review novel NDDS design strategies, based on the unique morphological and molecular signatures of liquid (myeloid leukemia) and solid tumors.…”