Abstract
Metastasis is one of most lethal causes that confer a poor prognosis of patients with esophageal squamous cell carcinoma (ESCC), whereas there is no available target drug for metastatic ESCC currently. In this study, we aimed to determine whether the transcriptional inhibition by CDK7/9 inhibitor SNS-032 is activity against ESCC. MTT and soft agar assays were performed to examine the influence of SNS-032 on ESCC growth in vitro. Tumor xenograft in nude mice was used to assess the antitumor activity of SNS-032 in vivo. The roles of SNS-032 in ESCC metastasis were conducted by wound healing and transwell assays in vitro, and by a lung and a popliteal lymph node metastasis model in vivo. The results showed that CDK7 and CDK9 were highly expressed in ESCC cells; SNS-032 effectively inhibited cellular viability, abrogated anchorage-independent growth, and potentiated the sensitivity to cisplatin in ESCC cells in vitro and in vivo. In addition, SNS-032 induced a mitochondrial-dependent apoptosis of ESCC cells by reducing Mcl-1 transcription. SNS-032 also potently abrogated the abilities of ESCC cell migration and invasion through transcriptional downregulation of MMP-1. Importantly, SNS-032 remarkably inhibited the growth of ESCC xenograft, increased the overall survival, as well as diminished the lung and lymph node metastasis in nude mice. Taken together, our findings highlight that the CDK7/9 inhibitor SNS-032 is a promising therapeutic agent, and warrants a clinical trial for its efficacy in ESCC patients, even those with metastasis.
Highlights
According to the GLOBOCAN estimates from the International Agency for Research on Cancer, esophageal cancer is the seventh most commonly diagnosed cancer, with an estimated 604,000 new cases, and is the sixth leading cause of cancer death (544,000 deaths) in 2020 [1]
Considering that SNS-032 is a selective inhibitor of CDK7 and CDK9 by blocking the phosphorylation of RNA polymerase II (Pol II) at Ser 2, 5, and 7, we examined whether SNS-032 inhibited the kinase activity of CDK7 and CDK9
In this study, we discovered that both CDK7 and CDK9 are highly elevated in all five tested human esophageal squamous cell carcinoma (ESCC) cells, suggesting existence of elevated transcription activity
Summary
According to the GLOBOCAN estimates from the International Agency for Research on Cancer, esophageal cancer is the seventh most commonly diagnosed cancer, with an estimated 604,000 new cases, and is the sixth leading cause of cancer death (544,000 deaths) in 2020 [1]. As the most common histologic subtypes of esophageal cancer, esophageal squamous cell carcinoma (ESCC) is highly prevalent in the South-East and Central Asian region, especially in China, which contributes >50% of worldwide cases [1]. The diagnosis, staging, and therapeutic strategies for ESCC have improved in recent years, the prognosis remains poor. The overall 5-year survival rate in ESCC patients with stage III disease is about 10% and the median survival time in patients with stage IV disease is
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
