Inhibition of KLF4 by Statins Reverses Adriamycin-Induced Metastasis and Cancer Stemness in Osteosarcoma Cells

Abstract

SummaryAdriamycin-based combination chemotherapy is the standard first-line treatment for osteosarcoma, but tumor recurrence and metastasis occurs in most cases. Recent evidence suggests that microenvironmental stress such as chemotherapy can lead to the enrichment of cancer stem cells (CSCs), which result in cancer metastasis, recurrence, and drug resistance. However, the exact mechanisms underlying this phenomenon and how to target CSCs are still open questions. Herein, we report that Adriamycin treatment induces a stem-like phenotype and promotes metastatic potential in osteosarcoma cells through upregulating KLF4. KLF4 knockdown blocks Adriamycin-induced stemness phenotype and metastasis capacity. We further screen that statins remarkably reverse Adriamycin-induced CSC properties and metastasis by downregulating KLF4. Most strikingly, simvastatin severely impaired Adriamycin-enhanced tumorigenesis of KHOS/NP cells in vivo. These data suggest that Adriamycin-based chemotherapeutics may simulate CSCs through activation of KLF4 signaling and that selective inhibition of KLF4 with statins should be considered in the development of osteosarcoma therapeutics.

Increased MALAT1 expression contributes to cisplatin resistance in non‑small cell lung cancer

“…Cancer stem cells are only a small proportion of the tumor cell population, and are crucial for tumor cell metastasis and drug resistance ( 28 , 29 ). As a key transcription factor in regulating cell reprogramming and an important gene in the maintenance of cancer cell stemness ( 30 , 31 ), KLF4 has been suggested to be associated with chemotherapy resistance in various types of cancer, including NSCLC ( 18 , 32 ). A previous study identified that following benzo[a]pyrene treatment, an increase in KLF4 and MALAT1 protein levels was detected during the malignant transformation of the human bronchial epithelial BEAS-2B cell line ( 33 ).…”

KLF4K409Q–mutated meningiomas show enhanced hypoxia signaling and respond to mTORC1 inhibitor treatment

“…The search of public databases for compound candidates that directly inhibit KLF4, revealed statins as a promising option. They are a well-established class of drugs with a good safety profile which have been shown to be cytotoxic against meningioma cells [10] and were recently reported to act as specific inhibitors of KLF4 in cancer stem cells [19]. Unfortunately, the effect of Simvastatin (a medication in Statins class) did not translate into our KLF4 meningioma model (Fig.…”

“…Its highly contextdependent function in tumor biology renders it a challenging, but in many tumor-entities promising therapeutic target [31,33,34,36,39]. Indeed, some KLF4 inhibitors, for instance Statins, have been already identified and recently characterized as promising inhibitory agents in osteosarcoma [6,19,44].…”

CCN2 promotes drug resistance in osteosarcoma by enhancing ABCG2 expression

“…Other evidence has also shown a positive correlation between the upregulation of chemoresistance and increased metastatic ability of osteosarcoma cells (Y. Li, Xian, Yang, Ying, & He, 2017;Palmini, Marini, & Brandi, 2017;Yan, Lv, & Guo, 2016). In contrast, it appears that ABCG2 protein expression is upregulated in colon cancer and its expression is decreased in the plasma membrane of colon cancer with metastasis of the lymphatic node metastasis (i.e., downregulated by 2.7-fold in N1 to N0; Wu et al, 2018).…”