Early decline in serum phospho-CSE1L levels in vemurafenib/sunitinib-treated melanoma and sorafenib/lapatinib-treated colorectal tumor xenografts

Abstract

BackgroundAlthough targeted therapies have improved the clinical outcomes of cancer treatment, tumors resistance to targeted drug are often detected too late and cause mortality. CSE1L is secreted from tumor and its phosphorylation is regulated by ERK1/2. ERK1/2 is located downstream of various growth factor receptors and kinases, the targets of most targeted drugs. Serum phospho-CSE1L may be a marker for monitoring the efficacy of targeted therapy.MethodsWe used mice tumor xenograft model to study the assay of serum phosphorylated CSE1L for early detecting the efficacy of targeted drugs. The phosphorylation status of CSE1L in vemurafenib and sorafenib treated tumor cells were assayed by immunoblotting with antibody against phosphorylated CSE1L.ResultsRas activation increased phospho-CSE1L expression in B16F10 melanoma cells. Vemurafenib and sorafenib treatment did not significantly reduce the total CSE1L levels; however, they inhibited ERK1/2 and CSE1L phosphorylation in A375 melanoma cells and HT-29 colorectal cancer cells. In the melanoma xenograft model, serum phospho-CSE1L level declined 5 days after vemurafenib/sunitinib treatment and 3 days after sorafenib/lapatinib treatment in the HT-29 colon cancer xenograft model. Vemurafenib/sunitinib and sorafenib/lapatinib treatments resulted in tumor regression.ConclusionsOur results indicated that serum phospho-CSE1L is useful for early detecting the efficacy of targeted therapy in initial treatment and for monitoring emerging secondary drug resistance to facilitate timely therapeutic decision making.

Antitumor activity of melinjo (Gnetum gnemon L.) seed extract in human and murine tumor models in vitro and in a colon‐26 tumor‐bearing mouse model in vivo

“…Animal models are extremely critical to assess the efficacy of antitumor agents in the preclinical settings. The subcutaneous colon tumor models are still used to evaluate treatment efficacy against colon tumor growth , including tumor metastasis to the liver . The colon‐26 mouse model, whereby the murine colon‐26 cells are injected subcutaneously into the flank of mice, is commonly used to study the effects of several antitumor agents, including dietary agents .…”

CSE1L Links cAMP/PKA and Ras/ERK pathways and regulates the expressions and phosphorylations of ERK1/2, CREB, and MITF in melanoma cells

“…Although the melanoma cells we studied harbor Ras mutations that were through v-H-Ras but not N-Ras expression, v-H-Ras induced the phosphorylations of ERK1/2 and MITF (Figures 3-5), and induced the melanogenesis (Figure 1) and metastasis of melanoma cells [24,29]. We have previously reported that Ras activation in melanoma cells induces CSE1L phosphorylation, indicating a link between Ras/Raf/MEK/ERK pathway and CSE1L in cancer progression [24,40]. In our current study, we showed that CSE1L knockdown decreased Ras-induced CREB, MITF, and tyrosinase expressions, in spite of the presence of IBMX ( Figure 5).…”

FLVCR1 Predicts Poor Prognosis and Promotes Malignant Phenotype in Esophageal Squamous Cell Carcinoma via Upregulating CSE1L

“…However, more comprehensive and in-depth studies are needed in our next plan to explore the precise molecular mechanisms involved in interactions between FLVCR1 and CSE1L. Besides, CSE1L can be detected not only in tumor tissues but also in body fluids, especially in the blood, indicating that CSE1L can be used as a tumor serum biomarker (20)(21)(22). Therefore, our further research plan is to investigate the diagnostic and prognostic value of serum CSE1L in ESCC.…”