Background Pulmonary fibrosis is a chronic and progressive disease that originates from interstitial lung diseases and ultimately exhibits respiratory failure in patients. The disease is characterized by focal accumulation and excessive production of extracellular matrix (ECM) from over-activated fibroblasts in the lung. Although many extrinsic factors have been identified to boost fibroblast proliferation and activation, it remains unclear how fibrosis is regulated by intrinsic factors. Methods Pulmonary fibrosis mouse model was induced by intratracheal injection of bleomycin (BLM) into CREPTWT and CREPTKO mice. In vitro study, the proliferation of mouse lung fibroblasts (MLFs) was assessed using CCK-8 assays and expression of fibrotic protein was examined following transforming growth factor (TGF)-β stimulation in MLFs. Results In this study, we found that deletion of CREPT alleviated BLM induced pulmonary fibrosis. Deletion of CREPT resulted in attenuated murine lung fibroblast proliferation, TGF-β-induced fibroblast-to-myofibroblast activation, and ECM deposition. Consistently, deletion of CREPT decreased the expression of fibrotic marker genes such as a-SMA, Col1a1, and FN1 but had no influence on the inflammation response upon the BLM challenge. Conclusions In summary, we report that CREPT is required for BLM induced pulmonary fibrosis in mice. Our study unravels an intrinsic molecular mechanism for the development of pulmonary fibrosis and provides a new target for the therapy of the interstitial lung disease.

Natural compounds that interfere with tumor cell growth have potential to be used as therapeutic agents to treat cancers. Lachnochromonin (p71) is a small molecule isolated from Lachnum virgineum. Here, we reported the effect of p71 on human tumor cells, especially on breast cancer MCF-7 cells. We found that p71 significantly suppresses cell growth and induces apoptosis. The luciferase results demonstrated that p71 specifically attenuates the activation of JAK/STAT3 signaling. Biochemical analysis revealed that p71 blocks the phosphorylation of STAT3 tyrosine 705 and serine 727, resulting in down-regulation of c-Myc and Cyclin D1 expression level. Importantly, p71 inhibited cell growth, colony-formation, and migration through affecting STAT3 activity. These results implied that p71 may be used as a therapeutic agent against breast cancer.

The invention discloses a polypeptide inhibitor for degrading CREPT and application thereof in inhibiting pancreatic cancer cell proliferation and tumorigenesis. The polypeptide inhibitor PRTC for degrading CREPT provided by the invention comprises a targeting module TA, a degradation module DA, a connecting body and a transmembrane peptide; the amino acid sequence of the targeting module TA is aprotein shown in the 266th-286th sites of the amino acid sequence of a CREPT protein; the amino acid sequence of the degradation module DA is a protein shown as a sequence 3; the connecting body is 6-aminocaproic acid; and the amino acid sequence of the transmembrane peptide is a protein shown as a sequence 4. The invention utilizes a targeted protein degradation chimeric technology, and designs and prepares the PRTC capable of degrading the CREPT protein through a proteasome pathway. Experiments prove that the PRTC can inhibit the proliferation and migration capacity of pancreatic cancer cells, reduce the tumorigenicity of the pancreatic cancer cells and provide a new thought for the treatment of pancreatic cancer.

Cancers remain a threat to human health due to the lack of effective therapeutic strategies. Great effort has been devoted to the discovery of drug targets to treat cancers, but novel oncoproteins still need to be unveiled for efficient therapy. Methods: We show that CREPT is highly expressed in pancreatic cancer and is associated with poor disease-free survival. CREPT overexpression promotes but CREPT deletion blocks colony formation and proliferation of pancreatic cancer cells. To provide a proof of concept for CREPT as a new target for the inhibition of pancreatic cancer, we designed a cell-permeable peptide-based proteolysis targeting chimera (PROTAC), named PRTC, based on the homodimerized leucine-zipper-like motif in the C-terminus domain of CREPT to induce its degradation in vivo. Results: PRTC has high affinity for CREPT, with Kd = 0.34 +/- 0.11 μM and is able to permeate into cells because of the attached membrane-transportable peptide RRRRK. PRTC effectively induces CREPT degradation in a proteasome-dependent manner. Intriguingly, PRTC inhibits colony formation, cell proliferation, and motility in pancreatic cancer cells and ultimately impairs xenograft tumor growth, comparable to the effect of CREPT deletion. Conclusions: PRTC-induced degradation of CREPT leads to inhibition of tumor growth, which is promising for the development of new drugs against pancreatic cancer. In addition, using an interacting motif based on the dimerized structure of proteins may be a new way to design a PROTAC aiming at degrading any protein without known interacting small molecules or peptides.