The multi-functional cytokine transforming growth factor-β1 (TGF-β1) has growth inhibitory and anti-inflammatory roles during homeostasis and the early stages of cancer. Aberrant TGF-β activation in the late-stages of tumorigenesis, however, promotes development of aggressive growth characteristics and metastatic spread. Given the critical importance of this growth factor in fibrotic and neoplastic disorders, the TGF-β1 network is subject to extensive, multi-level negative controls that impact receptor function, mothers against decapentaplegic homolog 2/3 (SMAD2/3) activation, intracellular signal bifurcation into canonical and non-canonical pathways and target gene promotor engagement. Such negative regulators include phosphatase and tensin homologue (PTEN), protein phosphatase magnesium 1A (PPM1A), Klotho, bone morphogenic protein 7 (BMP7), SMAD7, Sloan-Kettering Institute proto-oncogene/ Ski related novel gene (Ski/SnoN), and bone morphogenetic protein and activin membrane-bound Inhibitor (BAMBI). The progression of certain cancers is accompanied by loss of expression, overexpression, mislocalization, mutation or deletion of several endogenous repressors of the TGF-β1 cascade, further modulating signal duration/intensity and phenotypic reprogramming. This review addresses how their aberrant regulation contributes to cellular plasticity, tumor progression/metastasis and reversal of cell cycle arrest and discusses the unexplored therapeutic value of restoring the expression and/or function of these factors as a novel approach to cancer treatment.

Collagen type XI alpha 1 (COL11A1) is a novel biomarker associated with cisplatin resistance in ovarian cancer. We have previously reported that COL11A1 activates Src-Akt signaling through the collagen receptors discoidin domain receptor 2 (DDR2) and integrin α1β1 to confer cisplatin resistance to ovarian cancer cells. To identify the potential signaling molecules downstream of COL11A1 signaling, we performed protein kinase arrays and identified heat shock protein 27 (HSP27) as a potential mediator of COL11A1-induced cisplatin resistance. Through receptor knockdown and inhibitor experiments, we demonstrated that COL11A1 significantly upregulates HSP27 phosphorylation and expression via DDR2/integrin α1β1 and Src/Akt signaling in ovarian cancer cells. Furthermore, genetic knockdown and pharmacological inhibition of HSP27, via ivermectin treatment, significantly sensitizes ovarian cancer cells cultured on COL11A1 to cisplatin treatment. HSP27 knockdown or inhibition also decreases NFκB activity as well as the expression of inhibitors of apoptosis proteins (IAPs), which are known downstream effector molecules of COL11A1 that promote cisplatin resistance. Interestingly, HSP27 knockdown or inhibition stimulates ovarian cancer cells to upregulate fatty acid oxidation (FAO) for survival and cisplatin resistance, and dual inhibition of HSP27 and FAO synergistically kills ovarian cancer cells that are cultured on COL11A1. Collectively, this study identifies HSP27 as a novel and druggable COL11A1 downstream effector molecule that may be targeted to overcome cisplatin resistance in recurrent ovarian cancer, which often overexpress COL11A1.

Maladaptive tubular repair is a major contributor to fibrosis and chronic kidney disease (CKD), yet the molecular regulators of this process remain poorly understood. We report that the E3 ubiquitin ligases WWP1 and TRIM65 are novel regulators of tubular fibrosis. Both ligases were markedly induced in human and experimental CKD. WWP1 induction correlates with declining renal function in humans, highlighting the potential clinical relevance of WWP1. Profibrotic factor PAI-1 promotes a robust induction of WWP1 and TRIM65 in both primary human renal epithelial cells as well as cell line (HK-2). The silencing of WWP1 or TRIM65 significantly attenuated PAI-1-induced fibrotic signaling. Mechanistically, PAI-1 triggers a signaling cascade in which suppression of the regenerative BMP-7/SMAD5 pathway permits c-Myc induction, resulting in WWP1 and TRIM65 upregulation. The elevated expression of these ligases subsequently promotes epithelial dedifferentiation and fibrotic growth arrest. Restoration of BMP-7 or SMAD5 signaling disrupted this cascade and reduced fibrosis in renal tubular cells. Our study establishes a previously unrecognized PAI-1–c-Myc–WWP1/TRIM65 axis governing tubular maladaptive repair and positions WWP1 as a potentially new therapeutic target for slowing CKD progression.