Progranulin promotes Temozolomide resistance of glioblastoma by orchestrating DNA repair and tumor stemness

Abstract

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults with a dismal prognosis. Current therapy of surgical removal combined with Temozolomide (TMZ) and radiation therapy only slightly prolongs the survival of GBM patients. Thus, it is essential to elucidate mechanism underlying its highly malignant properties in order to develop efficacious therapeutic regimens. In this study, we showed that progranulin (PGRN) was overexpressed in most GBM cell lines and the majority of human tumor samples. PGRN overexpression conferred GBM cells with tumorigenic properties and TMZ resistance by upregulating DNA repair (PARP, ATM, BRCA1, Rad51, XRCC1 and so on) and cancer stemness (CD133, CD44, ABCG2) genes, in part via an AP-1 transcription factor, specifically cFos/JunB. Curcumin, an AP-1 inhibitor, was also found to regulate PGRN promoter activity and expression including its downstream effectors aforementioned. These data suggested a feedforward loop between PGRN signaling and AP-1. PGRN depletion significantly decreased unlimited self-renewal and multilineage differentiation and the malignant properties of GBMs cells S1R1, and enhanced their vulnerability to TMZ. In addition, S1R1 depleted of PGRN also lost the ability to form tumor in an orthotopic xenograft mouse model. In conclusion, PGRN had a critical role in the pathogenesis and chemoresistance of GBM and functioned at the top of the hierarchy of cellular machinery that modulates both DNA repair pathways and cancer stemness. Our data suggest that a new strategy combining current regimens with compounds targeting PGRN/AP-1 loop like curcumin may significantly improve the therapeutic outcome of GBM.

Therapeutic Potential of Curcumin for the Treatment of Brain Tumors

“…Data also exists to suggest that curcumin might affect tumoral stem cell-like populations [16, 46, 97]. These stem cell-like features are found in nestin and CD133 positive cells are associated with higher grade and poor prognosis [46, 98, 99]. Adding curcumin to other chemotherapeutic regimens may aid in slowing or halting growth of these progenitor cells and thus their tumors.…”

“…Interestingly, NF- κ B is found to be overstimulated in cisplatin-resistant C6 cells and NF- κ B inhibitors were able to overcome cisplatin resistance [45]. Similarly, progranulin has been found to be overexpressed in many GBM cell lines (U87, GBM8904, and S1R1) and tumor samples [46]. Progranulin overexpression contributes to tumorigenesis and treatment resistance by upregulating DNA repair and stemness genes using the transcription factor AP-1.…”

“…Progranulin overexpression contributes to tumorigenesis and treatment resistance by upregulating DNA repair and stemness genes using the transcription factor AP-1. Curcumin is an AP-1 inhibitor, and it was found to downregulate progranulin promoter activity and expression [46]. Other studies have shown that curcumin can reduce GBM cell survival through inhibition of AP-1 and NF- κ B by preventing constitutive activation of JNK and AKT [47].…”

Suppression of progranulin expression inhibits bladder cancer growth and sensitizes cancer cells to cisplatin

“…However, recent data in glioblastoma have demonstrated a role of progranulin in promoting Temozolomide resistance through the regulation of DNA repair and tumor cell stemness [38]. Future experiments will be devoted to characterize the role that progranulin may play in modulating DNA damage/repair in urothelial cancer cells.…”

Progranulin and its biological effects in cancer

“…In a more recent study with glioblastoma multiforme cells, PGRN overproduction induced resistance to temozolomide (alkylating agent) by upregulation of DNA repair genes PARP, serine/threonine kinase ATM, BRCA1, Rad51, and X-ray repair cross-complementing gene 1 (XRCC1) as well as enhanced expression of cancer stemness genes CD133, CD44 and ABCG2, through the activation of AP-1 transcription factor, specifically cFos/JunB [73]. …”