TY - JOUR
T1 - Novel LIPA-Targeted Therapy for Treating Ovarian Cancer
AU - Collier, Alexia B.
AU - Viswanadhapalli, Suryavathi
AU - Gopalam, Rahul
AU - Lee, Tae Kyung
AU - Kassees, Kara
AU - Parra, Karla
AU - Sharma, Gaurav
AU - Reese, Tanner C.
AU - Liu, Xihui
AU - Yang, Xue
AU - Ebrahimi, Behnam
AU - Pratap, Uday P.
AU - Mahajan, Megharani
AU - Arnold, William C.
AU - Baker, Adriana
AU - Chen, Chia Yuan
AU - Elmore, Scott Terry
AU - Subbarayalu, Panneerdoss
AU - Sareddy, Gangadhara R.
AU - Valente, Philip T.
AU - Kost, Edward R.
AU - Ahn, Jung Mo
AU - Vadlamudi, Ratna K.
N1 - Publisher Copyright:
© 2024 by the authors.
PY - 2024/2
Y1 - 2024/2
N2 - Ovarian cancer (OCa) is the most lethal form of gynecologic cancer, and the tumor heterogeneities at the molecular, cellular, and tissue levels fuel tumor resistance to standard therapies and pose a substantial clinical challenge. Here, we tested the hypothesis that the heightened basal endoplasmic reticulum stress (ERS) observed in OCa represents an exploitable vulnerability and may overcome tumor heterogeneity. Our recent studies identified LIPA as a novel target to induce ERS in cancer cells using the small molecule ERX-41. However, the role of LIPA and theutility of ERX-41 to treat OCa remain unknown. Expression analysis using the TNMplot web tool, TCGA data sets, and immunohistochemistry analysis using a tumor tissue array showed that LIPA is highly expressed in OCa tissues, compared to normal tissues. ERX-41 treatment significantly reduced the cell viability and colony formation ability and promoted the apoptosis of OCa cells. Mechanistic studies revealed a robust and consistent induction of ERS markers, including CHOP, elF2α, PERK, and ATF4, upon ERX-41 treatment. In xenograft and PDX studies, ERX-41 treatment resulted in a significant reduction in tumor growth. Collectively, our results suggest that ERX-41 is a novel therapeutic agent that targets the LIPA with a unique mechanism of ERS induction, which could be exploited to treat heterogeneity in OCa.
AB - Ovarian cancer (OCa) is the most lethal form of gynecologic cancer, and the tumor heterogeneities at the molecular, cellular, and tissue levels fuel tumor resistance to standard therapies and pose a substantial clinical challenge. Here, we tested the hypothesis that the heightened basal endoplasmic reticulum stress (ERS) observed in OCa represents an exploitable vulnerability and may overcome tumor heterogeneity. Our recent studies identified LIPA as a novel target to induce ERS in cancer cells using the small molecule ERX-41. However, the role of LIPA and theutility of ERX-41 to treat OCa remain unknown. Expression analysis using the TNMplot web tool, TCGA data sets, and immunohistochemistry analysis using a tumor tissue array showed that LIPA is highly expressed in OCa tissues, compared to normal tissues. ERX-41 treatment significantly reduced the cell viability and colony formation ability and promoted the apoptosis of OCa cells. Mechanistic studies revealed a robust and consistent induction of ERS markers, including CHOP, elF2α, PERK, and ATF4, upon ERX-41 treatment. In xenograft and PDX studies, ERX-41 treatment resulted in a significant reduction in tumor growth. Collectively, our results suggest that ERX-41 is a novel therapeutic agent that targets the LIPA with a unique mechanism of ERS induction, which could be exploited to treat heterogeneity in OCa.
KW - ERX-41
KW - LIPA
KW - endoplasmic reticulum stress
KW - lysosomal acid lipase A
KW - ovarian cancer
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U2 - 10.3390/cancers16030500
DO - 10.3390/cancers16030500
M3 - Article
C2 - 38339252
AN - SCOPUS:85184715685
SN - 2072-6694
VL - 16
JO - Cancers
JF - Cancers
IS - 3
M1 - 500
ER -