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Knockdown of human serine/threonine kinase 33 suppresses human small cell lung carcinoma by blocking RPS6/BAD

E L Sun, C X Liu, Z X Ma

|September 13, 2017

Abstract:

Small cell lung cancer (SCLC) is characterized by rapid growth rate and a tendency to metastasize to distinct sites of patients' bodies. The human serine/threonine kinase 33 (STK33) gene has shown its potency as a therapeutic target for prevention of lung carcinomas including non-small cell lung cancer (NSCLC), but its function in the oncogenesis and development of SCLC remains unrevealed. In the current study, it was hypothesized that STK33 played a key role in the proliferation, survival, and invasion of SCLC cells. The expression of STK33 in human SCLC cell lines NCI-H466 and DMS153 was inhibited by specific shRNA. The cell proliferation, cell apoptosis, and cell invasion of the cells were assessed with a series of in vitro assays. To explore the mechanism through which STK33 gene exerted its function in the carcinogenesis of SCLC cells, the effect of STK33 knockdown on the activity of S6K1/RPS6/BAD signaling was detected. Then the results were further confirmed with STK33 inhibitor ML281 and in vivo assays. The results demonstrated that inhibition of STK33 in SCLC cells suppressed the cell proliferation and invasion while induced cell apoptosis. Associated with the change in the phenotypic features, knockdown of STK33 also decreased the phosphorylation of RPS6 and BAD while increased the expression of cleaved caspase 9, indicating that apoptosis induced by STK33 suppression was mediated via mitochondrial pathway. Similar to the results of STK33 knockdown, incubating NCI-H466 cells with STK33 inhibitor also reduced the cell viability by suppressing RPS6/BAD pathways. Additionally, STK33 knockdown also inhibited tumor growth and RPS6/BAD activity in mice models. Findings outlined in our study were different from that in NSCLC to some extent: knockdown of STK33 in SCLC cells induced the apoptosis through mitochondrial pathway but independent of S6K1 function, inferring that the function of STK33 might be cancer type specific.

Insights

Inhibition of serine/threonine kinase 33 (STK33) suppresses small cell lung cancer (SCLC) growth by inducing apoptosis via the mitochondrial pathway. STK33

Area of Science:

Oncology
Molecular Biology
Cancer Research

Background:

Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options.
The role of serine/threonine kinase 33 (STK33) in SCLC oncogenesis is largely unknown.
STK33 is a potential therapeutic target in other lung cancers, but its specific function in SCLC requires elucidation.

Purpose of the Study:

To investigate the role of STK33 in the proliferation, survival, and invasion of SCLC cells.
To explore the underlying molecular mechanisms of STK33's function in SCLC.
To evaluate STK33 as a potential therapeutic target for SCLC.

Main Methods:

STK33 gene expression was inhibited in SCLC cell lines (NCI-H466, DMS153) using shRNA.
In vitro assays assessed cell proliferation, apoptosis, and invasion.
Western blotting detected changes in S6K1/RPS6/BAD signaling pathway activity.
STK33 inhibitor ML281 and in vivo mouse models were used for further validation.

Main Results:

STK33 inhibition significantly suppressed SCLC cell proliferation and invasion.
Knockdown of STK33 induced apoptosis through the mitochondrial pathway, evidenced by increased cleaved caspase 9.
STK33 inhibition decreased RPS6 and BAD phosphorylation, impacting cell survival.
In vivo studies confirmed that STK33 knockdown inhibited tumor growth in mice.

Conclusions:

STK33 plays a critical role in SCLC cell proliferation, invasion, and survival.
Targeting STK33 induces apoptosis via the mitochondrial pathway in SCLC.
STK33's function in SCLC appears distinct from its role in NSCLC, suggesting cancer-type specificity.

Read full analysis

Keywords:

BAD RPS6 small cell lung cancer.cleaved caspase 9 human serine/threonine kinase 33

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