PRKAR1A is a functional tumor suppressor inhibiting ERK/Snail/E-cadherin pathway in lung adenocarcinoma

Abstract

Protein Kinase cAMP-Dependent Regulatory Type I Alpha (PRKAR1A) is a tissue-specific extinguisher that transduces a signal through phosphorylation of different target proteins. Loss of PRKAR1A was frequently observed in endocrine neoplasia and stromal cell tumors. However, a few cases were seen in epithelial tumors. Previously, we first found that PRKAR1A was downregulated in lung adenocarcinoma patients. Thus, the present study aimed to clarify its clinical implication and biological function as a tumor suppressor in lung adenocarcinoma. The low levels of PRKAR1A transcript were correlated with tumor progression and poor overall survival. The re-expression of PRKAR1A in H1299 cells suppressed the tumor cell proliferation and migration; stable knockdown (KD) of PRKAR1A in A549 cells enhanced this function both in vitro and in vivo. Moreover, KD of PRKAR1A in A549 cells promoted the statistical colonization of circulating tumor cells to the lungs in nude mice. These effects by PRKAR1A were attributed to inhibiting E-cadherin expression. Elevated E-cadherin significantly suppressed the PRKAR1A-KD induced cell proliferation and migration. Most notably, deletion of PRKAR1A inhibited E-cadherin by activating ERK/Snail signaling. In conclusion, PRKAR1A was a potent suppressor, and through the inhibition of PRKAR1A-ERK-Snail-E-cadherin axis could serve as a potential therapeutic target.

RET Gene Fusions in Malignancies of the Thyroid and Other Tissues

“…Accordingly, several RET fusion partners have been shown to exert relevant homeostatic functions (Table 1). PRKAR1A, one of the RET fusion partners, is the tumor suppressor protein involved in inheritance of Carney complex, a tumor-prone syndrome [90]. Similarly, another RET fusion partner, NCOA4, is a multifunctional protein that is involved in the regulation of DNA synthesis by inhibiting replication origin activation.…”

Convergent Identification and Interrogation of Tumor-Intrinsic Factors that Modulate Cancer Immunity In Vivo

“…Reports have shown that Prkar1a knockout increases PKA activity, as well as resistance to apoptosis via mTOR activation (Robinson-White et al, 2006;Pringle et al, 2014). Additionally, it has also been shown that Prkar1a regulates the ERK, Snail and E-cadherin pathways (Wang et al, 2016). We investigated the mechanistic mechanisms of Prkar1a in cancer cells, showing that its genetic perturbation leads to drastic alterations in the proteome, phosphoproteome, and the transcriptome.…”

“…In this context, hereditary or germline LOF mutations in Prkar1a were sufficient to produce the disease in a dominant manner. In addition, Prkar1a mutations are associated with several tumor types such as cardiac, endocrine, thyroid, and lung adenocarcinoma (Kondo et al, 2017;Wang et al, 2016) (Saloustros et al, 2017). Prkar1a overexpression is also associated with tumor formation in multiple contexts, indicating that altering Prkar1a function leads to differential phenotypes across cellular and genetic backgrounds.…”

SH2B1 promotes epithelial‐mesenchymal transition through the IRS1/β‐catenin signaling axis in lung adenocarcinoma

“…Mice were randomly divided into groups ( n = 5 per group) before injection. The invasion effect of SH2B1 on LADC progression was examined in a lung colonization model . Two groups were injected with shSH2B1 transduced A549 cells or control A549 cells (1 × 10 6 cells in 0.1 ml phosphate‐buffered saline) via lateral tail veins.…”

“…The invasion effect of SH2B1 on LADC progression was examined in a lung colonization model. 42 Two groups were injected with shSH2B1 transduced A549 cells or control A549 cells (1 × 10 6 cells in 0.1 ml phosphate-buffered saline) via lateral tail veins. Another two groups were intravenously injected with stable SH2B1-overexpressing or control H1299 cells.…”