Urokinase-type plasminogen activator (uPA) is critical for progression of tuberous sclerosis complex 2 (TSC2)-deficient tumors

Abstract

Lymphangioleiomyomatosis (LAM) is a fatal lung disease associated with germline or somatic inactivating mutations in tuberous sclerosis complex genes ( or ). LAM is characterized by neoplastic growth of smooth muscle-α-actin-positive cells that destroy lung parenchyma and by the formation of benign renal neoplasms called angiolipomas. The mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin slows progression of these diseases but is not curative and associated with notable toxicity at clinically effective doses, highlighting the need for better understanding LAM's molecular etiology. We report here that LAM lesions and angiomyolipomas overexpress urokinase-type plasminogen activator (uPA). and mouse embryonic fibroblasts expressed higher uPA levels than their WT counterparts, resulting from the TSC inactivation. Inhibition of uPA expression in -null cells reduced the growth and invasiveness and increased susceptibility to apoptosis. However, rapamycin further increased uPA expression in TSC2-null tumor cells and immortalized TSC2-null angiomyolipoma cells, but not in cells with intact TSC. Induction of glucocorticoid receptor signaling or forkhead box (FOXO) 1/3 inhibition abolished the rapamycin-induced uPA expression in TSC-compromised cells. Moreover, rapamycin-enhanced migration of TSC2-null cells was inhibited by the uPA inhibitor UK122, dexamethasone, and a FOXO inhibitor. uPA-knock-out mice developed fewer and smaller TSC2-null lung tumors, and introduction of uPA shRNA in tumor cells or amiloride-induced uPA inhibition reduced tumorigenesis These findings suggest that interference with the uPA-dependent pathway, when used along with rapamycin, might attenuate LAM progression and potentially other TSC-related disorders.

SIRT1 inhibits chemoresistance and cancer stemness of gastric cancer by initiating an AMPK/FOXO3 positive feedback loop

“…4b, c). In the in vivo tumorigenicity assays, inhibitors were used to suppress the activities of AMPK and/or FOXO3 17 . Consistent with the in vitro findings, suppressing both AMPK and FOXO3 in SIRT1-overexpressing xenograft tumors substantially reversed the improved cisplatin sensitivity, as indicated by the tumor volumes and TUNEL staining ( Fig.…”

Possible Novel Therapeutic Targets in Lymphangioleiomyomatosis Treatment

“…The abnormal expression of the uPA system has been detected in breast cancer, prostate cancer, ovarian cancer, and lung cancer ( 84 ), and was recently reported in TSC-deficient tumors. The study found that overexpression of uPA was a direct consequence of TSC mutation in LAM cells and mTOR inhibitors even increased expression of uPA in cells with compromised TSC function ( 85 ). However, inhibition of uPA expression in TSC2-null tumor cells could not only reduce their invasive and mitogenic potentials but also increase their susceptibility to the pro-apoptotic agent simvastatin ( 85 ).…”

“…The study found that overexpression of uPA was a direct consequence of TSC mutation in LAM cells and mTOR inhibitors even increased expression of uPA in cells with compromised TSC function ( 85 ). However, inhibition of uPA expression in TSC2-null tumor cells could not only reduce their invasive and mitogenic potentials but also increase their susceptibility to the pro-apoptotic agent simvastatin ( 85 ). Together, these studies indicate that uPA might serve as a potential target to prevent the dissemination of tumor cells and the progression of disease in LAM treatment.…”

Systemic and topical administration of spermidine accelerates skin wound healing

“…A previous study demonstrated that amiloride inhibited the uPA-uPAR pathway in a mouse lung tumor model [17]. Next, to determine whether the uPA-uPAR pathway contributes to the ability of SPD to promote skin wound healing, we intraperitoneally administered amiloride (10 mg/kg) daily.…”